Bioabsorbable biomedical implants

ABSTRACT

A bioabsorbable biomedical implant is disclosed. The implant includes a tubular scaffold comprising a plurality of interconnected polymer struts. The interconnected polymer struts defines a plurality of deformable cells. The polymer struts have an average thickness of no more than 150 μm. Methods for making the bioabsorbable biomedical implant, including the methods for making the fiber-reinforced polymer composite materials for the tubular scaffold, are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/823,755, filed May 15, 2013, the content of which is herebyincorporated by reference in its entirety.

BACKGROUND

The present disclosure relates to bioabsorbable stents made of polymericcomposite materials and method of manufacturing the bioabsorbablestents.

SUMMARY OF THE DISCLOSURE

According to one aspect of the present disclosure, a biomedical implantis disclosed as including a tubular scaffold comprising a plurality ofinterconnected polymer struts. The interconnected polymer struts definesa plurality of deformable cells. The polymer struts have an averagethickness of no more than 150 μm. Also provided is a biomedical implant,comprising: a tubular scaffold comprising a plurality of polymer struts,wherein the polymer struts are interconnected and define a plurality ofdeformable cells, wherein the polymer struts have an average thicknessof no more than 150 μm, and wherein the polymer struts comprise afiber-reinforced polymer composite material. In some embodiments, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg. In another embodiment,the tubular scaffold maintains at least 80% of its nominal luminal crosssectional area under a pressure load of 50 mmHg. In some embodiments,the tubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg upon 3 months ofexposure to saline in vitro. In another embodiment, the tubular scaffoldmaintains at least 50% of its deployed luminal cross sectional areaunder a pressure load of 50 mmHg upon 3 months in vivo. In someembodiments, the tubular scaffold maintains at least 50% of its nominalluminal cross sectional area under a pressure load of 50 mmHg upon 6months of exposure to saline in vitro. In another embodiment, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg upon 6 months in vivo.In some embodiments, at least 80% of the polymer struts are bioabsorbedwithin 2 years after deployment in vivo. In another embodiment, at least80% of the polymer struts are bioabsorbed within 1 year after deploymentin vivo. In some embodiments, the polymer struts have an averagethickness of no more than 120 μm. In another embodiment, the polymerstruts have an average thickness of no more than 90 μm. In someembodiments, the polymer struts have anisotropic elastic modulus. In arefinement, the polymer struts have an average longitudinal (i.e. alongthe axis of the polymer struts) elastic modulus and an average lateralelastic modulus, the average longitudinal elastic modulus being greaterthan the average lateral elastic modulus. In a further refinement, theaverage longitudinal elastic modulus is at least three times the averagelateral elastic modulus. In another further refinement, the averagelongitudinal elastic modulus is at least five times the average lateralelastic modulus. In yet another further refinement, the averagelongitudinal elastic modulus is at least ten times the average lateralelastic modulus. In some embodiments, the polymer struts includereinforcement fibers that are longitudinally (i.e. along the axis of thepolymer struts) aligned. In some embodiments, more than 50% of thereinforcement fibers in the polymer struts are longitudinally aligned.In another embodiment, more than 70% of the reinforcement fibers in thepolymer struts are longitudinally aligned. In another embodiment, morethan 90% of the reinforcement fibers in the polymer struts arelongitudinally aligned. In some embodiments, the polymer struts have anaverage deformation angle of at least 60 degrees. In another embodiment,the polymer struts have an average deformation angle of at least 45degrees. In some embodiments, the polymer struts comprises afiber-reinforced polymer composite material. In some embodiments, thefiber-reinforced polymer composite material comprises a bioabsorbablepolymer material and a reinforcement fiber material. In someembodiments, the reinforcement fiber material is carbon fiber material,carbon nanotube material, bioabsorbable glass material, or combinationsthereof. In some embodiments, the carbon nanotube material is amulti-wall carbon nanotube material. In some embodiments, thereinforcement fiber material comprises one or more surfacefunctionalities to facilitate intermolecular interaction between thebioabsorbable polymer material and the reinforcement fiber material. Insome embodiments, the one or more surface functionalities are selectedfrom —COOH, —OH, or combination thereof. In some embodiments, thereinforcement fiber material comprising one or more surfacefunctionalities is multi-wall carbon nanotube material. In someembodiments, the reinforcement fiber material is distributed throughoutthe polymer struts. In some embodiments, the fiber-reinforced polymercomposite material has a tensile modulus that is at least five times ofa tensile modulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile modulus thatis at least three times of a tensile modulus of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile modulus that is at least two times of a tensilemodulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile strength thatis at least five times of a tensile strength of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile strength that is at least three times of atensile strength of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile strength thatis at least two times of a tensile strength of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial comprises from 0.1 wt % to 15 wt % of the reinforcement fibermaterial. In some embodiments, the fiber-reinforced polymer compositematerial comprises from 0.1 wt % to 10 wt % of the reinforcement fibermaterial. In some embodiments, the fiber-reinforced polymer compositematerial comprises from 0.1 wt % to 5 wt % of the reinforcement fibermaterial. In some embodiments, the fiber-reinforced polymer compositematerial comprises from 0.1 wt % to 1.5 wt % of the reinforcement fibermaterial. In some embodiments, the bioabsorbable polymer material isselected from the group consisting of polylactides (PLA);poly(lactide-co-glycolide) (PLGA); polyanhydrides; polyorthoesters;poly(N-(2-hydroxypropyl) methacrylamide); poly(dl-lactide) (DLPLA);poly(l-lactide) (LPLA); poly(d-lactide) (DPLA); polyglycolide (PGA);poly(dioxanone) (PDO); poly(glycolide-co-trimethylene carbonate)(PGA-TMC); poly(l-lactide-co-glycolide) (PGA-LPLA);poly(dl-lactide-co-glycolide) (PGA-DLPLA); poly(l-lactide-co-dl-lactide)(LPLA-DLPLA); poly(glycolide-co-trimethylene carbonate-co-dioxanone)(PDO-PGA-TMC), poly(lactic acid-co-caprolactone) (PLACL), and mixturesor co-polymers thereof. In one refinement, the bioabsorbable polymermaterial is PLGA. In a further refinement, the PLGA has a ratio oflactic acid monomer to glycolic acid monomer ranging from 72:28 to78:22. In another further refinement, the PLGA has a ratio of lacticacid monomer to glycolic acid monomer ranging from 62:38 to 68:32. Inanother further refinement, the PLGA has a ratio of lactic acid monomerto glycolic acid monomer ranging from 47:53 to 53:47. In another furtherrefinement, the PLGA has a weight average molecular weight of about8,000 Dalton to about 12,000 Dalton. In another further refinement, thePLGA has a weight average molecular weight of about 12,000 Dalton toabout 16,000 Dalton. In another further refinement, the PLGA has aweight average molecular weight of up to about 90,000 Dalton. In anotherrefinement, the bioabsorbable polymer material is PLA or LPLA. Inanother refinement, the bioabsorbable polymer material is PGA. In someembodiment, the bioabsorbable polymer material (e.g. PLGA, LPLA, PLA,PGA) has a weight average molecular weight of at least 90,000 Dalton,and optionally at least 100,000 Dalton. In some embodiments, the polymerstruts include a polymer material selected from the group consisting ofpolycarboxylic acids, cellulosic polymers, proteins, polypeptides,polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinylalcohols, polyethylene oxides, glycosaminoglycans, polysaccharides,polyesters, aliphatic polyesters, polyurethanes, polystyrenes,copolymers, silicones, silicone containing polymers, polyalkylsiloxanes, polyorthoesters, polyanhydrides, copolymers of vinylmonomers, polycarbonates, polyethylenes, polypropytenes, polylacticacids, polylactides, polyglycolic acids, polyglycolides,polylactide-co-glycolides, polycaprolactones, poly(e-caprolactone)s,polyhydroxybutyrate valerates, polyacrylamides, polyethers, polyurethanedispersions, polyacrylates, acrylic latex dispersions, polyacrylic acid,polyalkyl methacrylates, polyalkylene-co-vinyl acetates, polyalkylenes,aliphatic polycarbonates polyhydroxyalkanoates, polytetrahaloalkylenes,poly(phosphasones), polytetrahaloalkylenes, poly(phosphasones), andmixtures, combinations, and copolymers thereof. In some embodiments, thetubular scaffold is expandable from an undeployed diameter to a nominaldiameter without affecting the structural integrity of the tubularscaffold. In a refinement, the tubular scaffold is further expandablefrom the nominal diameter to an over-deployed diameter without affectingthe structural integrity of the tubular scaffold. In a furtherrefinement, the over-deployed diameter is about 1.0 mm greater than thenominal diameter. In another further refinement, the over-deployeddiameter is about 0.5 mm greater than the nominal diameter. In onerefinement, the tubular scaffold is expandable by an inflatable balloonpositioned within the tubular scaffold. In a further refinement, thetubular scaffold has a nominal diameter of 2.25 mm at nominal balloonpressure. In another further refinement, the tubular scaffold has anominal diameter of 2.5 mm at nominal balloon pressure. In anotherfurther refinement, the tubular scaffold has a nominal diameter of 3.0mm at nominal balloon pressure. In another further refinement, thetubular scaffold has a nominal diameter of 3.5 mm at nominal balloonpressure. In another further refinement, the tubular scaffold has anominal diameter of 4.0 mm at nominal balloon pressure. In anotherfurther refinement, the tubular scaffold has a nominal diameter of 4.5mm at nominal balloon pressure. In one refinement, the polymer strutscomprise a shape-memory polymer and wherein tubular scaffold isself-expandable. In a further refinement, the tubular scaffold isself-expandable upon change in temperature. In another furtherrefinement, the tubular scaffold is self-expandable upon change incrystallinity of the shape-memory polymer. In some embodiments, thetubular scaffold is formed from a plurality of sinusoidal polymer fiberseach including a plurality of struts. In a refinement, the sinusoidalpolymer fibers are interconnected at a plurality of connecting points.In some embodiments, the tubular scaffold is formed from a singlepolymer fiber including a plurality of struts. In a refinement, thesingle polymer fiber comprises a plurality of sinusoidal sectionsinterconnected at a plurality of connecting points. In some embodiments,the biomedical implant further includes a pharmaceutical agentincorporated to the tubular scaffold. In a refinement, thepharmaceutical agent is a macrolide immunosuppressant. In a furtherrefinement, the macrolide immunosuppressant is rapamycin or aderivative, a prodrug, a hydrate, an ester, a salt, a polymorph, aderivative or an analog thereof. In another further refinement, themacrolide immunosuppressant is selected from the group consisting ofrapamycin, 40-O-(2-Hydroxyethyl)rapamycin, (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin,40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin,40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin,40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin,40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin. In onerefinement, the pharmaceutical agent is rapamycin. In one refinement,the pharmaceutical agent is impregnated in at least a portion of thetubular scaffold. In a further refinement, the pharmaceutical agent isimpregnated in the polymer struts. In a further refinement, thepharmaceutical agent is evenly distributed throughout the polymerstruts. In one refinement, at least a portion of the tubular scaffold iscovered with a coating comprising the pharmaceutical agent. In a furtherrefinement, the coating further comprises a coating polymer. In afurther refinement, at least 90% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, the coating polymer comprises a bioabsorbablepolymer. In a further refinement, the bioabsorbable polymer is selectedfrom the group consisting of polylactides (PLA);poly(lactide-co-glycolide) (PLGA); polyanhydrides; polyorthoesters;poly(N-(2-hydroxypropyl) methacrylamide); poly(dl-lactide) (DLPLA);poly(l-lactide) (LPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),polyarginine, and mixtures or co-polymers thereof. In a furtherrefinement, the biodegradable polymer is selected from the groupconsisting of PLGA, polyarginine, and mixtures thereof. In someembodiments, the biomedical implant is a vascular stent. In anotherembodiment, the biomedical implant is a coronary artery stent. Inanother embodiment, the biomedical implant is a peripheral artery stent.In another embodiment, the biomedical implant is a non-vascular stent.In a refinement, the non-vascular stent is selected from esophagealstent, biliary stent, duodenal stent, colonic stent, and pancreaticstent. According to another aspect of the present disclosure, a methodof forming a biomedical implant is disclosed. The method includes thesteps of forming one or more polymer fibers comprising a bioabsorbablepolyester material and a reinforcement fiber material; andinterconnecting the polymer fibers to form a tubular scaffold, thetubular scaffold comprising a plurality of interconnected polymer strutsto define a plurality of deformable cells, wherein the polymer strutshave an average thickness of no more than 150 μm. In some embodiments,the tubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of at least 50 mmHg. In someembodiments, the tubular scaffold maintains at least 80% of its nominalluminal cross sectional area under a pressure load of at least 50 mmHg.In some embodiments, the reinforcement fiber material is carbon fibermaterial, carbon nanotube material, bioabsorbable glass material, orcombinations thereof. In some embodiments, the carbon nanotube materialis a multi-wall carbon nanotube material. In some embodiments, thereinforcement fiber material comprises one or more surfacefunctionalities to facilitate intermolecular interaction between thebioabsorbable polymer material and the reinforcement fiber material. Insome embodiments, the one or more surface functionalities are selectedfrom —COOH, —OH, or combination thereof. In some embodiments, thereinforcement fiber material comprising one or more surfacefunctionalities is multi-wall carbon nanotube material. In someembodiments, the polymer fibers comprise from 0.1 wt % to 15 wt % of thereinforcement fiber material. In some embodiments, the polymer fiberscomprise from 0.1 wt % to 10 wt % of the reinforcement fiber material.In some embodiments, the polymer fibers comprise from 0.1 wt % to 5 wt %of the reinforcement fiber material. In some embodiments, the polymerfibers comprise from 0.1 wt % to 1.5 wt % of the reinforcement fibermaterial.

In some embodiments, the polyester is selected from the group consistingof polylactides (PLA); poly(lactide-co-glycolide) (PLGA);polyanhydrides; polyorthoesters; poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA);poly(d-lactide) (DPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),poly(lactic acid-co-caprolactone) (PLACL), and mixtures or co-polymersthereof. In some embodiments, the polyester is PLGA. In someembodiments, the polyester is PLA or LPLA. According to another aspectof the present disclosure, another method of making a bioabsorbabletubular scaffold is disclosed. The method includes the steps of forminga composition comprising a bioabsorbable polyester material and areinforcement fiber material; extruding the composition to form apolymer tube, wherein the polymer tube has an average wall thickness ofno more than 150 μm; and removing a portion of the polymer tube to forma scaffold comprising interconnected struts. In some embodiments, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of at least 50 mmHg. In someembodiments, the tubular scaffold maintains at least 80% of its nominalluminal cross sectional area under a pressure load of at least 50 mmHg.In some embodiments, the reinforcement fiber material is carbon fibermaterial, carbon nanotube material, bioabsorbable glass material, orcombinations thereof. In some embodiments, the carbon nanotube materialis a multi-wall carbon nanotube material. In some embodiments, thereinforcement fiber material comprises one or more surfacefunctionalities to facilitate intermolecular interaction between thebioabsorbable polymer material and the reinforcement fiber material. Insome embodiments, the one or more surface functionalities are selectedfrom —COOH, —OH, or combination thereof. In some embodiments, thereinforcement fiber material comprising one or more surfacefunctionalities is multi-wall carbon nanotube material. In someembodiments, the polymer tube comprises from 0.1 wt % to 15 wt % of thereinforcement fiber material. In some embodiments, the polymer tubecomprises from 0.1 wt % to 10 wt % of the reinforcement fiber material.In some embodiments, the polymer tube comprises from 0.1 wt % to 5 wt %of the reinforcement fiber material. In some embodiments, the polymertube comprises from 0.1 wt % to 1.5 wt % of the reinforcement fibermaterial. In some embodiments, the polyester is selected from the groupconsisting of polylactides (PLA); poly(lactide-co-glycolide) (PLGA);polyanhydrides; polyorthoesters; poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA);poly(d-lactide) (DPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),poly(lactic acid-co-caprolactone) (PLACL), and mixtures or co-polymersthereof. In some embodiments, the polyester is PLGA. In someembodiments, the polyester is PLA or LPLA. In some embodiments, theremoving is selected from laser-cutting, photochemical etching, andwater-jetting.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the present disclosure may be implemented, orall the features that may be added to the present disclosure. Forexample, features illustrated with respect to one embodiment may beincorporated into other embodiments, and features illustrated withrespect to a particular embodiment may be deleted from that embodiment.In addition, numerous variations and additions to the variousembodiments suggested herein will be apparent to those skilled in theart in light of the instant disclosure, which do not depart from thepresent disclosure. Hence, the following specification is intended toillustrate some particular embodiments of the present disclosure, andnot to exhaustively specify all permutations, combinations andvariations thereof.

Bioabsorbable Biomedical Implant

Bioabsorbable biomedical implants, such as stents made of polymerswithout metal structural reinforcements, provide several desirablefeatures over metal-based biomedical implants. Yet, the development ofbioabsorbable polymer stents remains challenging to this date. Asbioabsorbable polymer materials used to make the polymer stents aregenerally weaker than metals (e.g. steel), polymer stents withstructural strength and integrity similar to metal stents need to bemade of polymer struts with average thickness much greater than that ofthe metal struts (e.g. greater or significantly greater than 150 μm).

It is contemplated in the present disclosure that the increased strutthickness, while improving the structural strength and integrity of thestents, may adversely affect one or more desirable characteristics ofthe polymer stent. For example, the thicker struts may result in a stentwith larger overall stent profile and less flexibility, and hence moredifficult to navigate within blood vessels before deployment. Thethicker struts may also lead to lower deformability that limits range ofdeployment (e.g. less than 10% overexpansion above nominal diameter, orless than about 0.5 mm in a vascular stent). In addition, the thickerstruts may take longer to be fully dissolved or degraded, such asbetween three to five years.

According to one aspect of the present disclosure, a biomedical implantis disclosed as including a tubular scaffold comprising a plurality ofinterconnected polymer struts. The interconnected polymer struts definesa plurality of deformable cells. The polymer struts have an averagethickness of no more than 150 μm.

Average Strut Thickness

In some embodiments, the polymer struts have an average thickness of nomore than 150 μm. In another embodiment, the polymer struts have anaverage thickness of no more than 140 μm. In another embodiment, thepolymer struts have an average thickness of no more than 130 μm. Inanother embodiment, the polymer struts have an average thickness of nomore than 120 μm. In another embodiment, the polymer struts have anaverage thickness of no more than 110 μm. In another embodiment, thepolymer struts have an average thickness of no more than 100 μm. Inanother embodiment, the polymer struts have an average thickness of nomore than 90 μm. In another embodiment, the polymer struts have anaverage thickness of no more than 80 μm. In another embodiment, thepolymer struts have an average thickness of no more than 70 μm. Inanother embodiment, the polymer struts have an average thickness of nomore than 60 μm. In another embodiment, the polymer struts have anaverage thickness of no more than 50 μm.

In some embodiments, the polymer struts have an average thickness offrom 50 μm to about 150 μm. In some embodiments, the polymer struts havean average thickness of from 60 μm to about 150 μm. In some embodiments,the polymer struts have an average thickness of from 70 μm to about 150μm. In some embodiments, the polymer struts have an average thickness offrom 80 μm to about 150 μm. In some embodiments, the polymer struts havean average thickness of from 90 μm to about 150 μm. In some embodiments,the polymer struts have an average thickness of from 100 μm to about 150μm. In some embodiments, the polymer struts have an average thickness offrom 110 μm to about 150 μm. In some embodiments, the polymer strutshave an average thickness of from 120 μm to about 150 μm.

In some embodiments, the polymer struts have an average thickness offrom 50 μm to about 120 μm. In some embodiments, the polymer struts havean average thickness of from 60 μm to about 120 μm. In some embodiments,the polymer struts have an average thickness of from 70 μm to about 120μm. In some embodiments, the polymer struts have an average thickness offrom 80 μm to about 120 μm. In some embodiments, the polymer struts havean average thickness of from 90 μm to about 120 μm.

In some embodiments, the polymer struts have an average thickness offrom 50 μm to about 100 μm. In some embodiments, the polymer struts havean average thickness of from 60 μm to about 100 μm. In some embodiments,the polymer struts have an average thickness of from 70 μm to about 100μm. In some embodiments, the polymer struts have an average thickness offrom 80 μm to about 100 μm. In some embodiments, the polymer struts havean average thickness of from 90 μm to about 100 μm.

In some embodiments, the polymer struts have an average thickness offrom 50 μm to about 90 μm. In some embodiments, the polymer struts havean average thickness of from 60 μm to about 90 μm. In some embodiments,the polymer struts have an average thickness of from 70 μm to about 90μm. In some embodiments, the polymer struts have an average thickness offrom 80 μm to about 90 μm.

Structural Strength and Integrity

The structural strength and integrity of the disclosed bioabsorbablebiomedical implants can be characterized by one or combinations of thefollowing methods.

Radial Strength Testing

This test is conducted to determine and graphically represent the changein stent internal diameter as a function of circumferential pressure andto determine the pressure at which deformation is no longer completelyreversible for the disclosed stent. The stents are deployed to nominalpressure and removed from the delivery system. The stents are placedinto a sleeve approximately lmm larger than the stent diameter. A vacuumis then applied and outer diameter measurements taken at variouspressures. The bioabsorbable implants according to the presentdisclosure should maintain a minimum of at least 50 percent of theoriginal stent diameter after a 50 mm Hg pressure is applied. Somebioabsorbable implants according to the present disclosure shouldmaintain a minimum of at least 80 percent of the original stent diameterafter a 50 mm Hg pressure is applied.

Stent Recoil Testing

This test was conducted to quantify the amount of elastic recoil. Thestent delivery system is inflated to nominal pressure (9 ATM) and thestent is removed allowing for recoil to occur. The inner diameter ateach end of the stent is recorded. Recoil is calculated subtracting therecoiled stent inner diameter from the pre-recoil inner diameter.

Stent Expansion Testing

This test is conducted to determine if the plastic deformationexperienced by the stent when expanded from the compressed profile tothe final maximum deployed diameter (i.e. over-deployed diameter) canproduce crack initiation for the disclosed stent. The sample stents aredeployed to their largest possible diameters by inflating each deliverysystem to balloon failure. Each stent is examined at 45× magnificationfor potential cracks.

Maximum Pressure (Burst Test) Testing

This test is conducted to demonstrate that the delivery system (withmounted stent) will not experience balloon, shaft, proximal adaptationor proximal/distal seal loss of integrity at or below the pressurerequired to expand the stent to its labeled diameter. Stent deliverysystems that had been subjected to all manufacturing and sterilizationprocedures were pressurized to 90 psi with pressure held for 15 secondsand released for 3 seconds. The cycle was then repeated, increasinginflation pressure by 15 psi each cycle until failure.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of 50 mmHg.In another embodiment, the tubular scaffold maintains at least 60% ofits nominal luminal cross sectional area under a pressure load of 50mmHg. In another embodiment, the tubular scaffold maintains at least 70%of its nominal luminal cross sectional area under a pressure load of 50mmHg. In another embodiment, the tubular scaffold maintains at least 80%of its nominal luminal cross sectional area under a pressure load of 50mmHg. In another embodiment, the tubular scaffold maintains at least 90%of its nominal luminal cross sectional area under a pressure load of 50mmHg. In another embodiment, the tubular scaffold maintains at least 95%of its nominal luminal cross sectional area under a pressure load of 50mmHg.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of 50 mmHgupon 2 months of exposure to saline in vitro. In another embodiment, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg upon 2 month in vivo.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of 50 mmHgupon 3 months of exposure to saline in vitro. In another embodiment, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg upon 3 month in vivo.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of 50 mmHgupon 4 months of exposure to saline in vitro. In another embodiment, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg upon 4 month in vivo.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of 50 mmHgupon 6 months of exposure to saline in vitro. In another embodiment, thetubular scaffold maintains at least 50% of its nominal luminal crosssectional area under a pressure load of 50 mmHg upon 6 month in vivo.

Reinforcement Fiber Materials

In some embodiments, the polymer struts comprises a fiber-reinforcedpolymer composite material. In a refinement, the fiber-reinforcedpolymer composite material comprises a bioabsorbable polymer materialand a reinforcement fiber material. In a further refinement, thereinforcement fiber material is carbon fiber material or carbon nanotubematerial.

In some embodiments, the carbon nanotube material is a multi-wall carbonnanotube material.

In some embodiments, the reinforcement fiber material is distributedthroughout the polymer struts.

Carbon Fiber

Carbon fiber (sometimes also referred to as graphite fiber, carbongraphite or CF), is a material consisting of fibers about 5-10 μm indiameter and composed mostly of carbon atoms. The carbon atoms arebonded together in crystals that are more or less aligned parallel tothe long axis of the fiber. The crystal alignment gives the fiber highstrength-to-volume ratio (making it strong for its size). Severalthousand carbon fibers are bundled together to form a tow, which may beused by itself or woven into a fabric.

Each carbon filament thread is a bundle of many thousand carbonfilaments. A single such filament is a thin tube with a diameter of 5-8micrometers and consists almost exclusively of carbon. The earliestgeneration of carbon fibers (e.g. T300, HTA and AS4) had diameters of7-8 micrometers. Later fibers (e.g. IM6 or IM600) have diameters thatare approximately 5 micrometers.

The atomic structure of carbon fiber is similar to that of graphite,consisting of sheets of carbon atoms (graphene sheets) arranged in aregular hexagonal pattern. The difference lies in the way these sheetsinterlock. Graphite is a crystalline material in which the sheets arestacked parallel to one another in regular fashion. The intermolecularforces between the sheets are relatively weak Van der Waals forces,giving graphite its soft and brittle characteristics. Depending upon theprecursor to make the fiber, carbon fiber may be turbostratic orgraphitic, or have a hybrid structure with both graphitic andturbostratic parts present. In turbostratic carbon fiber the sheets ofcarbon atoms are haphazardly folded, or crumpled, together. Carbonfibers derived from Polyacrylonitrile (PAN) are turbostratic, whereascarbon fibers derived from mesophase pitch are graphitic after heattreatment at temperatures exceeding 2200 C. Turbostratic carbon fiberstend to have high tensile strength, whereas heat-treatedmesophase-pitch-derived carbon fibers have high Young's modulus (i.e.,high stiffness or resistance to extension under load) and high thermalconductivity. Major manufacturers of carbon fibers include Hexcel, SGLCarbon, Toho Tenax, Toray Industries and Zoltek. Manufacturers typicallymake different grades of fibers for different applications.

Carbon fibers are sometimes combined with other materials to form acomposite. When combined with a plastic resin and wound or molded itforms carbon fiber reinforced plastic which has a highstrength-to-weight ratio. However, the carbon-fiber reinforced polymercomposite also has a high rigidity and sometime a tendency to bebrittle, thereby limiting its use in devices and apparatus wheredeformability is desirable or mandatory, such as in deformable medicalimplants. It is contemplated that the technical features disclosedherein, whether alone or in various combinations, enables thedevelopment of a fiber-reinforced polymer composite material that hasimproved mechanical strength (e.g. tensile modulus and tensile strength)and yet has sufficient deformability for application in deformablemedical implants, such as stents. It is further contemplated that thetechnical features disclosed herein, whether alone or in variouscombinations, enables the development of a fiber-reinforcement polymercomposite material that is at least substantially bioabsorbable within adesirable period of time.

Carbon Nanotube

Carbon nanotubes (CNTs) are allotropes of carbon with a cylindricalnanostructure. Nanotubes have been constructed with length-to-diameterratio of up to 132,000,000:1, significantly larger than for any othermaterial. These cylindrical carbon molecules have unusual properties,which are valuable for nanotechnology, electronics, optics and otherfields of materials science and technology. In particular, owing totheir extraordinary thermal conductivity and mechanical and electricalproperties, carbon nanotubes find applications as additives to variousstructural materials.

Nanotubes are categorized as single-walled nanotubes (SWNTs) andmulti-walled nanotubes (MWNTs). Individual nanotubes naturally alignthemselves into “ropes” held together by van der Waals forces, morespecifically, pi-stacking. Multi-walled nanotubes (MWNT) consist ofmultiple rolled layers (concentric tubes) of graphene. There are twomodels that can be used to describe the structures of multi-wallednanotubes. In the Russian Doll model, sheets of graphite are arranged inconcentric cylinders, e.g., a (0,8) single-walled nanotube (SWNT) withina larger (0,17) single-walled nanotube. In the Parchment model, a singlesheet of graphite is rolled in around itself, resembling a scroll ofparchment or a rolled newspaper. The interlayer distance in multi-wallednanotubes is close to the distance between graphene layers in graphite,approximately 3.4 Å. The Russian Doll structure is observed morecommonly. Its individual shells can be described as SWNTs, which can bemetallic or semiconducting.

Carbon nanotubes have generally very high the strength and stiffness.They are sometimes combined with other materials to form a composite. Assuch, carbon nanotube reinforced polymer composite also has a highrigidity and sometime a tendency to be brittle, thereby limiting its usein devices and apparatus where deformability is desirable or mandatory,such as in deformable medical implants. It is contemplated that thetechnical features disclosed herein, whether alone or in variouscombinations, enables the development of a fiber-reinforced polymercomposite material that has improved mechanical strength (e.g. tensilemodulus and tensile strength) and yet has sufficient deformability forapplication in deformable medical implants, such as stents. It isfurther contemplated that the technical features disclosed herein,whether alone or in various combinations, enables the development of afiber-reinforcement polymer composite material that is at leastsubstantially bioabsorbable within a desirable period of time.

Bioabsorbable Glass

Another reinforcement fiber material suitable for the present disclosureis bioabsorbable glass material. In some embodiments, the bioabsorbableglass material is a spun or drawn glass fiber having the requiredtensile strength and resorption properties. As such, the glass fibersreinforce the bioabsorbable polymer matrix as the bioabsorbable polymerand the reinforcement glass fiber are gradually reduced in strength andelastic modulus, such as through slow, steady bioabsorption.

As a non-limiting example, the bioabsorbable glass material includes abinary mixture of calcium oxide (CaO) and phosphorous pentoxide (P₂O₅);although, other ingredients such as calcium fluoride (CaF₂), water(H₂O), and other oxides containing cations such as magnesium, zinc,strontium, sodium, potassium, lithium and aluminum may also beincorporated in small amounts. In terms of the binary mixture, thepreferred Ca:P mole ratio is 0.25 to 0.33. Preferably, the glasscomprises by weight 5-50% CaO, 50-95% P₂O₅, 0-5% CaF₂, 0-5% H₂O, and0-10% XO, wherein X is a single magnesium, zinc or strontium ion or twosodium, potassium, lithium or aluminum ions and O is a single oxygen ionexcept when X is aluminum, in which case it is three oxygen ions. Morepreferably, the calcium oxide (CaO) is present by weight in the amountof 15-25%; the phosphorous pentoxide (P₂O₅) is present by weight in theamount of 65-90%; and either calcium fluoride (CaF₂) or water (H₂O) ispresent by weight in the amount of 0.1-4%.

Surface Modification

In some embodiments, the reinforcement fiber material comprises one ormore surface functionalities to facilitate intermolecular interactionbetween the bioabsorbable polymer material and the reinforcement fibermaterial. In some embodiment, the reinforcement fibers are chemicallymodified to include the surface functionalities. Without wishing to bebound by any particular theory, it is contemplated that the surfacefunctionalities contribute to desirable reinforcement fiber orientation,desirable reinforcement fiber distribution or dispersion, and/or othertechnical features of the present disclosure.

In some embodiments, the one or more surface functionalities areselected from —COOH, —OH, or combination thereof. In some embodiments,the reinforcement fiber material comprising one or more surfacefunctionalities is multi-wall carbon nanotube material.

A non-limiting example of chemically modifying multi-wall carbonnanotube to include —COOH is provided in Li Buay Koh, Isabel Rodriguezb,Subbu S. Venkatramana. A novel nanostructuredpoly(lactic-co-glycolic-acid)-multi-walled carbon nanotube composite forblood-contacting applications: Thrombogenicity studies. ActaBiomaterialia Volume 5, Issue 9, November 2009, Pages 3411-3422.

A non-limiting example of chemically modifying multi-wall carbonnanotube to include —COOH or —OH is provided in Wu, C. S. & Liao, H. T.(2007). Study on the preparation and characterization of biodegradablepolylactide/multi-walled carbon nanotubes nanocomposites. Polymer, Vol.48, No. 15, (July 2007), pp. 4449-4458.

The contents of those articles are incorporated herein in theirentirety. Moreover, other method of adding surface functionalities toreinforcement fibers can be used in light of the technical featuredisclosed herein.

Method of Making Fiber-Reinforced Polymer Composite Material

Non-limiting examples of methods of making the fiber reinforced polymercomposite materials, especially bioabsorbable polymer compositematerials, are provided below.

-   Chlopek, J.; Morawska-Chochól, A.; Bajor, G.; Adwent, M.;    Cieślik-Bielecka, A.; Cieślik, M.; Sabat, D. The influence of carbon    fibres on the resorption time and mechanical properties of the    lactide-glycolide co-polymer. J. Biomater. Sci. Polym. Ed. 2007, 18,    1355-1368.-   Li Buay Koh, Isabel Rodriguezb, Subbu S. Venkatramana. A novel    nanostructured poly(lactic-co-glycolic-acid)-multi-walled carbon    nanotube composite for blood-contacting applications:    Thrombogenicity studies. Acta Biomaterialia Volume 5, Issue 9,    November 2009, Pages 3411-3422.-   Wu, C. S. & Liao, H. T. (2007). Study on the preparation and    characterization of biodegradable polylactide/multi-walled carbon    nanotubes nanocomposites. Polymer, Vol. 48, No. 15, (July 2007), pp.    4449-4458.-   Hualin Zhang. Electrospun poly(lactic-co-glycolic acid)/multiwalled    carbon nanotubes composite scaffolds for guided bone tissue    regeneration. Journal of Bioactive and Compatible Polymers 26(4)    347-362 2011

The contents of those articles are incorporated herein in theirentirety. Moreover, other method of making the fiber reinforced polymercomposite materials can be used in light of the technical featuredisclosed herein.

Tensile Modulus

In some embodiments, the inclusion of the reinforcement fiber materialsignificantly increases tensile modulus of the fiber-reinforced polymercomposite material. In some embodiments, the fiber-reinforced polymercomposite material has a tensile modulus that is at least ten times of atensile modulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile modulus thatis at least nine times of a tensile modulus of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile modulus that is at least eight times of a tensilemodulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile modulus thatis at least seven times of a tensile modulus of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile modulus that is at least six times of a tensilemodulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile modulus thatis at least five times of a tensile modulus of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile modulus that is at least four times of a tensilemodulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile modulus thatis at least three times of a tensile modulus of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile modulus that is at least two times of a tensilemodulus of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile modulus thatis at least 1.5 times of a tensile modulus of the bioabsorbable polymer.

Tensile Strength

In some embodiments, the inclusion of the reinforcement fiber materialsignificantly increases tensile strength of the fiber-reinforced polymercomposite material. In some embodiments, the fiber-reinforced polymercomposite material has a tensile strength that is at least ten times ofa tensile strength of the bioabsorbable polymer. In some embodiments,the fiber-reinforced polymer composite material has a tensile strengththat is at least nine times of a tensile strength of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile strength that is at least eight times of atensile strength of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile strength thatis at least seven times of a tensile strength of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile strength that is at least six times of a tensilestrength of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile strength thatis at least five times of a tensile strength of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile strength that is at least four times of a tensilestrength of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile strength thatis at least three times of a tensile strength of the bioabsorbablepolymer. In some embodiments, the fiber-reinforced polymer compositematerial has a tensile strength that is at least two times of a tensilestrength of the bioabsorbable polymer. In some embodiments, thefiber-reinforced polymer composite material has a tensile strength thatis at least 1.5 times of a tensile strength of the bioabsorbablepolymer.

Content of Reinforcement Fiber

In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 15 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 10 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 5 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 4 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 3 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 2 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 1.5 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 1 wt % of the reinforcement fiber material.

In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 0.9 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 0.9 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 0.8 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 0.7 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.1 wt % to 0.6 wt % of the reinforcement fiber material.

In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.2 wt % to 0.9 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.2 wt % to 0.9 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.2 wt % to 0.8 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.2 wt % to 0.7 wt % of the reinforcement fiber material.In some embodiments, the fiber-reinforced polymer composite materialcomprises from 0.2 wt % to 0.6 wt % of the reinforcement fiber material.

Reinforcement Fiber Orientation Strut-Longitudinal Orientation

In some embodiments, each polymer strut includes reinforcement fibersthat are longitudinally aligned along a center axis of the polymerstrut. In some embodiments, more than 50% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 55% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 60% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 65% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 70% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 75% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 80% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 85% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 90% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts. Insome embodiments, more than 95% of reinforcement fibers arelongitudinally aligned along the center axes of the polymer struts.

As a result of the strut-longitudinal reinforcement fiber orientation,the polymer struts have anisotropic elastic modulus. In someembodiments, the polymer struts have an average longitudinal elasticmodulus along the center axes of the polymer struts and an averagelateral elastic modulus orthogonal to the center axes of the polymerstruts, the average longitudinal elastic modulus being greater than theaverage lateral elastic modulus.

In one embodiment, the average longitudinal elastic modulus is at least2 times the average lateral elastic modulus. In another embodiment, theaverage longitudinal elastic modulus is at least 3 times the averagelateral elastic modulus. In another embodiment, the average longitudinalelastic modulus is at least 4 times the average lateral elastic modulus.In another embodiment, the average longitudinal elastic modulus is atleast 5 times the average lateral elastic modulus. In anotherembodiment, the average longitudinal elastic modulus is at least 6 timesthe average lateral elastic modulus. In another embodiment, the averagelongitudinal elastic modulus is at least 7 times the average lateralelastic modulus. In another embodiment, the average longitudinal elasticmodulus is at least 8 times the average lateral elastic modulus. Inanother embodiment, the average longitudinal elastic modulus is at least9 times the average lateral elastic modulus. In another embodiment, theaverage longitudinal elastic modulus is at least 10 times the averagelateral elastic modulus.

Scaffold-Axial Orientation

In one embodiment, the tubular scaffold includes reinforcement fibersthat are axially aligned along a center axis of the tubular scaffold. Insome embodiment, more than 50% of reinforcement fibers are axiallyaligned along a center axis of the tubular scaffold. In some embodiment,more than 55% of reinforcement fibers are axially aligned along a centeraxis of the tubular scaffold. In some embodiment, more than 60% ofreinforcement fibers are axially aligned along a center axis of thetubular scaffold. In some embodiment, more than 65% of reinforcementfibers are axially aligned along a center axis of the tubular scaffold.In some embodiment, more than 70% of reinforcement fibers are axiallyaligned along a center axis of the tubular scaffold. In some embodiment,more than 75% of reinforcement fibers are axially aligned along a centeraxis of the tubular scaffold. In some embodiment, more than 80% ofreinforcement fibers are axially aligned along a center axis of thetubular scaffold. In some embodiment, more than 85% of reinforcementfibers are axially aligned along a center axis of the tubular scaffold.In some embodiment, more than 90% of reinforcement fibers are axiallyaligned along a center axis of the tubular scaffold. In some embodiment,more than 95% of reinforcement fibers are axially aligned along a centeraxis of the tubular scaffold.

As a result of the scaffold-axial reinforcement fiber orientation, thetubular scaffold has anisotropic elastic modulus. In some embodiments,the tubular scaffold has an average axial elastic modulus along a centeraxis of the tubular scaffold and an average circumferential elasticmodulus orthogonally surrounding a center axis of the tubular scaffold,the average axial elastic modulus being greater than the averagecircumferential elastic modulus.

In one embodiment, the average axial elastic modulus is at least 2 timesthe average circumferential elastic modulus. In another embodiment, theaverage axial elastic modulus is at least 3 times the averagecircumferential elastic modulus. In another embodiment, the averageaxial elastic modulus is at least 4 times the average circumferentialelastic modulus. In another embodiment, the average axial elasticmodulus is at least 5 times the average circumferential elastic modulus.In another embodiment, the average axial elastic modulus is at least 6times the average circumferential elastic modulus. In anotherembodiment, the average axial elastic modulus is at least 7 times theaverage circumferential elastic modulus. In another embodiment, theaverage axial elastic modulus is at least 8 times the averagecircumferential elastic modulus. In another embodiment, the averageaxial elastic modulus is at least 9 times the average circumferentialelastic modulus. In another embodiment, the average axial elasticmodulus is at least 10 times the average circumferential elasticmodulus.

Scaffold-Circumferential Orientation

In one embodiment, the tubular scaffold includes reinforcement fibersthat are circumferential aligned, i.e. orthogonally surrounding a centeraxis of the tubular scaffold. In some embodiments, more than 50% ofreinforcement fibers are circumferential aligned. In some embodiments,more than 55% of reinforcement fibers are circumferential aligned. Insome embodiments, more than 60% of reinforcement fibers arecircumferential aligned. In some embodiments, more than 65% ofreinforcement fibers are circumferential aligned. In some embodiments,more than 70% of reinforcement fibers are circumferential aligned. Insome embodiments, more than 75% of reinforcement fibers arecircumferential aligned. In some embodiments, more than 80% ofreinforcement fibers are circumferential aligned. In some embodiments,more than 85% of reinforcement fibers are circumferential aligned. Insome embodiments, more than 90% of reinforcement fibers arecircumferential aligned. In some embodiments, more than 95% ofreinforcement fibers are circumferential aligned.

As a result of the scaffold-circumferential reinforcement fiberorientation, the tubular scaffold has anisotropic elastic modulus. Forexample, the tubular scaffold has an average axial elastic modulus alonga center axis of the tubular scaffold and an average radial elasticmodulus orthogonal to a center axis of the tubular scaffold, the averagecircumferential elastic modulus being greater than the average axialelastic modulus.

In one embodiment, the average circumferential elastic modulus is atleast 2 times the average axial elastic modulus. In another embodiment,the average circumferential elastic modulus is at least 3 times theaverage axial elastic modulus. In another embodiment, the averagecircumferential elastic modulus is at least 4 times the average axialelastic modulus. In another embodiment, the average circumferentialelastic modulus is at least 5 times the average axial elastic modulus.In another embodiment, the average circumferential elastic modulus is atleast 6 times the average axial elastic modulus. In another embodiment,the average circumferential elastic modulus is at least 7 times theaverage axial elastic modulus. In another embodiment, the averagecircumferential elastic modulus is at least 8 times the average axialelastic modulus. In another embodiment, the average circumferentialelastic modulus is at least 9 times the average axial elastic modulus.In another embodiment, the average circumferential elastic modulus is atleast 10 times the average axial elastic modulus.

Bioabsorbable Polymer Materials

In some embodiments, the polymer struts comprises a gel-spun polymermaterial. In a refinement, the polymer struts are not structurallyreinforced with a metal material. In a further refinement, the gel-spunpolymer material is selected from the group consisting of polylactides(PLA); poly(lactide-co-glycolide) (PLGA); polyanhydrides;polyorthoesters; poly(N-(2-hydroxypropyl) methacrylamide);poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA); poly(d-lactide)(DPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),poly(lactic acid-co-caprolactone) (PLACL), and mixtures or co-polymersthereof.

In one refinement, the gel-spun polymer material is PLGA. In a furtherrefinement, the PLGA has a ratio of lactic acid monomer to glycolic acidmonomer ranging from 82:18 to 88:12. In a further refinement, the PLGAhas a ratio of lactic acid monomer to glycolic acid monomer ranging from72:28 to 78:22. In another further refinement, the PLGA has a ratio oflactic acid monomer to glycolic acid monomer ranging from 62:38 to68:32. In another further refinement, the PLGA has a ratio of lacticacid monomer to glycolic acid monomer ranging from 47:53 to 53:47. Inanother further refinement, the PLGA has a ratio of lactic acid monomerto glycolic acid monomer of 50:50.

In another further refinement, the PLGA has a weight average molecularweight of about 8,000 Dalton to about 12,000 Dalton. In another furtherrefinement, the PLGA has a weight average molecular weight of about12,000 Dalton to about 16,000 Dalton. In another further refinement, thePLGA has a weight average molecular weight of up to about 90,000 Dalton.In another refinement, the gel-spun polymer material is PLA or LPLA. Inanother refinement, the gel-spun polymer material is PGA. In someembodiment, the gel spun polymer material (e.g. PLGA, LPLA, PLA, PGA)has a weight average molecular weight of at least 90,000 Dalton, andoptionally at least 100,000 Dalton

In some embodiments, the polymer struts include a polymer materialselected from the group consisting of polycarboxylic acids, cellulosicpolymers, proteins, polypeptides, polyvinylpyrrolidone, maleic anhydridepolymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, aliphatic polyesters,polyurethanes, polystyrenes, copolymers, silicones, silicone containingpolymers, polyalkyl siloxanes, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropytenes, polylactic acids, polylactides, polyglycolic acids,polyglycolides, polylactide-co-glycolides, polycaprolactones,poly(e-caprolactone)s, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polyurethane dispersions, polyacrylates, acrylic latexdispersions, polyacrylic acid, polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic polycarbonatespolyhydroxyalkanoates, polytetrahaloalkylenes, poly(phosphasones),polytetrahaloalkylenes, poly(phosphasones), and mixtures, combinations,and copolymers thereof.

Deformation Angle

Further, as a result of the polymer chain orientation, the polymerstruts have an average deformation angle, i.e. the average angle betweenthe polymer struts when deployed minus the average angle between thepolymer structs when undeployed. In some embodiments, the polymer strutshave an average deformation angle of at least 90 degrees. In anotherembodiment, the polymer struts have an average deformation angle of atleast 85 degrees. In another embodiment, the polymer struts have anaverage deformation angle of at least 80 degrees. In another embodiment,the polymer struts have an average deformation angle of at least 75degrees. In another embodiment, the polymer struts have an averagedeformation angle of at least 70 degrees. In another embodiment, thepolymer struts have an average deformation angle of at least 65 degrees.In another embodiment, the polymer struts have an average deformationangle of at least 60 degrees. In another embodiment, the polymer strutshave an average deformation angle of at least 55 degrees. In anotherembodiment, the polymer struts have an average deformation angle of atleast 50 degrees. In another embodiment, the polymer struts have anaverage deformation angle of at least 45 degrees. In another embodiment,the polymer struts have an average deformation angle of at least 40degrees. In another embodiment, the polymer struts have an averagedeformation angle of at least 30 degrees. Without wishing to be bound byany particular theory, it is contemplated that the configuration of thepolymer struts according to the specified deformation angle improves thedeformability of the polymer stent made of chain-oriented polymers.

Stent Deployment

In some embodiments, the tubular scaffold is expandable from anundeployed diameter to a nominal diameter without affecting thestructural integrity of the tubular scaffold. In a refinement, thetubular scaffold is further expandable from the nominal diameter to anover-deployed diameter without affecting the structural integrity of thetubular scaffold.

In a further refinement, the over-deployed diameter is about 1.0 mmgreater than the nominal diameter. In another further refinement, theover-deployed diameter is about 0.9 mm greater than the nominaldiameter. In another further refinement, the over-deployed diameter isabout 0.8 mm greater than the nominal diameter. In another furtherrefinement, the over-deployed diameter is about 0.7 mm greater than thenominal diameter. In another further refinement, the over-deployeddiameter is about 0.6 mm greater than the nominal diameter. In anotherfurther refinement, the over-deployed diameter is about 0.5 mm greaterthan the nominal diameter. In another further refinement, theover-deployed diameter is about 0.4 mm greater than the nominaldiameter. In another further refinement, the over-deployed diameter isabout 0.3 mm greater than the nominal diameter. In another furtherrefinement, the over-deployed diameter is about 0.2 mm greater than thenominal diameter.

In one refinement, the tubular scaffold is expandable by an inflatableballoon positioned within the tubular scaffold. In a further refinement,the tubular scaffold has a deployed diameter of 2.25 mm at nominalballoon pressure. In another further refinement, the tubular scaffoldhas a deployed diameter of 2.5 mm at nominal balloon pressure. Inanother further refinement, the tubular scaffold has a deployed diameterof 3.0 mm at nominal balloon pressure. In another further refinement,the tubular scaffold has a deployed diameter of 3.5 mm at nominalballoon pressure. In another further refinement, the tubular scaffoldhas a deployed diameter of 4.0 mm at nominal balloon pressure. Inanother further refinement, the tubular scaffold has a deployed diameterof 4.5 mm at nominal balloon pressure. The nominal balloon pressure maybe dependent on the material and design of the balloon. As anon-limiting example, the nominal balloon pressure is 6 atmospheres. Asanother example, the nominal balloon pressure is 9 atmosphere.

In one refinement, the polymer struts comprise a shape-memory polymerand wherein tubular scaffold is self-expandable. In a furtherrefinement, the tubular scaffold is self-expandable upon change intemperature. In another further refinement, the tubular scaffold isself-expandable upon change in crystallinity of the shape-memorypolymer.

In some embodiments, the tubular scaffold is formed from a plurality ofsinusoidal polymer fibers each including a plurality of struts. In arefinement, the sinusoidal polymer fibers are interconnected at aplurality of connecting points.

In some embodiments, the tubular scaffold is formed from a singlepolymer fiber including a plurality of struts. In a refinement, thesingle polymer fiber comprises a plurality of sinusoidal sectionsinterconnected at a plurality of connecting points.

Many methods for forming wire- or filament-based stents can be used tomake the bioabsorbable stents disclosed herein. For example, the methodsfor forming Wallstent (Boston Scientific), S7 (Medtronic), AngioStent(AngioDynamics), Strecker (Boston Scientific), Expander (Medicorp),Horizon Prostatic (Endocare), Endocoil (InStent), etc, can be used to inlight of the present disclosure.

Drug Incorporation

In some embodiments, the biomedical implant further includes apharmaceutical agent incorporated to the tubular scaffold. In arefinement, the pharmaceutical agent is a macrolide immunosuppressant.In a further refinement, the macrolide immunosuppressant is rapamycin ora derivative, a prodrug, a hydrate, an ester, a salt, a polymorph, aderivative or an analog thereof. In another further refinement, themacrolide immunosuppressant is selected from the group consisting ofrapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin,40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin,40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(25)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin,40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin,40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin. In onerefinement, the pharmaceutical agent is rapamycin.

In one refinement, the pharmaceutical agent is impregnated in at least aportion of the tubular scaffold. In a further refinement, thepharmaceutical agent is impregnated in the polymer struts. In a furtherrefinement, the pharmaceutical agent is evenly distributed throughoutthe polymer struts.

In some embodiment, the pharmaceutical agent is impregnated in thefiber-reinforced polymer composite material before composite materialforms the polymer struts or tubular scaffold. In some embodiments, thepharmaceutical agent is impregnated in the bioabsorbable polymer beforethe impregnated polymer is combined with the reinforcement fiber to formthe fiber-reinforced polymer composite material. In some embodiment, thepharmaceutical agent is combined with the bioabsorbable polymer andreinforcement fiber in the process of forming the fiber-reinforcedpolymer composite material.

In one refinement, at least a portion of the tubular scaffold is coveredwith a coating comprising the pharmaceutical agent. In a furtherrefinement, the coating further comprises a coating polymer. In afurther refinement, at least 90% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 85% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 80% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 75% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 70% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 65% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 60% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 55% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer. In afurther refinement, at least 50% of the surface area of thepharmaceutical agent is encapsulated in the coating polymer.

In a further embodiment, the pharmaceutical agent is impregnated in atleast a portion of the tubular scaffold (e.g. evenly distributedthroughout the tubular scaffold) and at least a portion of the tubularscaffold is covered with a coating comprising the pharmaceutical agent,such as in the manner discussed in the paragraph above.

In a further refinement, the coating polymer comprises a bioabsorbablepolymer. In a further refinement, the bioabsorbable polymer is selectedfrom the group consisting of polylactides (PLA);poly(lactide-co-glycolide) (PLGA); polyanhydrides; polyorthoesters;poly(N-(2-hydroxypropyl) methacrylamide); poly(dl-lactide) (DLPLA);poly(l-lactide) (LPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),polyarginine, and mixtures or co-polymers thereof. In a furtherrefinement, the biodegradable polymer is selected from the groupconsisting of PLGA, polyarginine, and mixtures thereof.

In some embodiments, the biomedical implant is a vascular stent. Inanother embodiment, the biomedical implant is a coronary artery stent.In another embodiment, the biomedical implant is a peripheral arterystent. In another embodiment, the biomedical implant is a non-vascularstent. In a refinement, the non-vascular stent is selected fromesophageal stent, biliary stent, duodenal stent, colonic stent, andpancreatic stent.

Manufacturing of Bioabsorbable Stent

According to another aspect of the present disclosure, a method offorming a biomedical implant is disclosed. The method includes the stepsof forming one or more polymer fibers comprising a bioabsorbablepolyester material and a reinforcement fiber material; andinterconnecting the polymer fibers to form a tubular scaffold, thetubular scaffold comprising a plurality of interconnected polymer strutsto define a plurality of deformable cells, wherein the polymer strutshave an average thickness of no more than 150 μm.

According to another aspect of the present disclosure, another method ofmaking a bioabsorbable tubular scaffold is disclosed. The methodincludes the steps of forming a composition comprising a bioabsorbablepolyester material and a reinforcement fiber material; extruding thecomposition to form a polymer tube, wherein the polymer tube has anaverage wall thickness of no more than 150 μm; and removing a portion ofthe polymer tube to form a scaffold comprising interconnected struts.

Manufacturing of Tubular Scaffold

Tubular Scaffold Made from Polymer Fiber(s)

According to another aspect of the present disclosure, a method offorming a biomedical implant is disclosed. The method includes the stepsof forming one or more polymer fibers comprising a bioabsorbablepolyester material and a reinforcement fiber material; andinterconnecting the polymer fibers to form a tubular scaffold, thetubular scaffold comprising a plurality of interconnected polymer strutsto define a plurality of deformable cells, wherein the polymer strutshave an average thickness of no more than 150 μm.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of at least50 mmHg. In some embodiments, the tubular scaffold maintains at least80% of its nominal luminal cross sectional area under a pressure load ofat least 50 mmHg.

In some embodiments, the reinforcement fiber material is a carbon fibermaterial or a carbon nanotube material. In some embodiments, the carbonnanotube material is a multi-wall carbon nanotube material.

In some embodiments, the polymer fibers comprise from 0.1 wt % to 15 wt% of the reinforcement fiber material. In some embodiments, the polymerfibers comprise from 0.1 wt % to 10 wt % of the reinforcement fibermaterial. In some embodiments, the polymer fibers comprise from 0.1 wt %to 5 wt % of the reinforcement fiber material. In some embodiments, thepolymer fibers comprise from 0.1 wt % to 1.5 wt % of the reinforcementfiber material.

In some embodiments, the polyester is selected from the group consistingof polylactides (PLA); poly(lactide-co-glycolide) (PLGA);polyanhydrides; polyorthoesters; poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA);poly(d-lactide) (DPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),poly(lactic acid-co-caprolactone) (PLACL), and mixtures or co-polymersthereof.

In some embodiments, the polyester is PLGA. In some embodiments, thepolyester is PLA or LPLA.

Tubular Scaffold Made with Polymer Tubes

According to another aspect of the present disclosure, another method ofmaking a bioabsorbable tubular scaffold is disclosed. The methodincludes the steps of forming a composition comprising a bioabsorbablepolyester material and a reinforcement fiber material; extruding thecomposition to form a polymer tube, wherein the polymer tube has anaverage wall thickness of no more than 150 μm; and removing a portion ofthe polymer tube to form a scaffold comprising interconnected struts.

In some embodiments, the tubular scaffold maintains at least 50% of itsnominal luminal cross sectional area under a pressure load of at least50 mmHg. In some embodiments, the tubular scaffold maintains at least80% of its nominal luminal cross sectional area under a pressure load ofat least 50 mmHg.

In some embodiments, the reinforcement fiber material is a carbon fibermaterial or a carbon nanotube material. In some embodiments, the carbonnanotube material is a multi-wall carbon nanotube material.

In some embodiments, the polymer tube comprises from 0.1 wt % to 15 wt %of the reinforcement fiber material. In some embodiments, the polymertube comprises from 0.1 wt % to 10 wt % of the reinforcement fibermaterial. In some embodiments, the polymer tube comprises from 0.1 wt %to 5 wt % of the reinforcement fiber material. In some embodiments, thepolymer tube comprises from 0.1 wt % to 1.5 wt % of the reinforcementfiber material.

In some embodiments, the polyester is selected from the group consistingof polylactides (PLA); poly(lactide-co-glycolide) (PLGA);polyanhydrides; polyorthoesters; poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA);poly(d-lactide) (DPLA); polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),poly(lactic acid-co-caprolactone) (PLACL), and mixtures or co-polymersthereof.

In some embodiments, the polyester is PLGA. In some embodiments, thepolyester is PLA or LPLA.

In some embodiments, the removing is selected from laser-cutting,photochemical etching, and water-jetting.

Coating Of Tubular Scaffold.

Provided herein are methods for coating the tubular scaffold (alsoreferred to as substrate in this section) with a pharmaceutical orbiological agent in powder form. Conventional processes for spraycoating stents may also be used. For example, the drug and coatingpolymer may be dissolved in a suitable solvent or mutual solvent beforespray coating can occur. Provided herein are methods for depositing acoating polymer and a pharmaceutical or biological agent in powder formonto the substrate. The coating process provides a cost-effective,efficient method for depositing a combination of an inert polymer orpolymers and a pharmaceutical or biological agent or agents, onto partsor all surfaces of a substrate, to form a coating that is of apre-determined, desired thickness, conformal, substantially defect-free,and uniform and the composition of the coating can be regulated. Inparticular, the coating process addresses the problem of existingcoating processes, which do not allow for structural and morphologicalpreservation of the agents deposited during the coating process.

One aspect of the invention entails the deposition of the pharmaceuticalor biological agents as dry powder. Dry powder spraying is well known inthe art, and dry powder spraying coupled with electrostatic capture hasbeen described, for example in U.S. Pat. Nos. 5,470,603; 6,319,541; or6,372,246. The deposition of the polymer can be performed in any numberof standard procedures, as the morphology of the polymer, so long as itprovides coatings possessing the desired properties (e.g. thickness,conformity, defect-free, uniformity etc), is of less importance. Thefunction of the polymer is primarily one of inert carrier matrix for theactive components of the coating.

One aspect of the coating process is the combination of two or more ofthe dry powder, RESS and SEDS spraying techniques.

Another aspect of the coating process involves the dry powder sprayingof a pharmaceutical agent, in a preferred particle size and morphology,into the same capture vessel as a polymer that is also dry powdersprayed, whereby the spraying of the agent and the polymer is sequentialor simultaneous.

Another specific aspect of the coating process involves the dry powderspraying of an active biological agent, in a preferred particle size andpossessing a particular activity, into the same capture vessel as apolymer that is also dry powder sprayed, whereby the spraying of theagent and the polymer is sequential or simultaneous.

Yet another aspect of the coating process involves the dry powderspraying of a pharmaceutical agent, in a preferred particle size andmorphology, into the same capture vessel as a polymer that issequentially or simultaneously sprayed by the RESS spray process.

Yet another aspect of the coating process involves the dry powderspraying of an active biological agent, in a preferred particle size andpossessing a particular activity, into the same capture vessel as apolymer that is sequentially or simultaneously sprayed by the RESS sprayprocess.

Yet another aspect of the coating process involves the dry powderspraying of a pharmaceutical agent, in a preferred particle size andmorphology, into the same capture vessel as a polymer that issequentially or simultaneously sprayed by the SEDS spray process.

Yet another aspect of the coating process involves the dry powderspraying of an active biological agent, in a preferred particle size andpossessing a particular activity, into the same capture vessel as apolymer that is sequentially or simultaneously sprayed by the SEDS sprayprocess.

In some embodiments, the RESS or the SEDS process used in forming thecoating is performed with electrically charging the substrate. In someembodiments, the e-RESS or the e-SEDS process used in forming thecoating is performed by creating an electrical potential between thesubstrate and the coating apparatus used in process. In some embodiment,the RESS or the SEDS process used in forming the coating is performedwithout electrically charging the substrate.

In further aspects of the coating process the substrates that have beencoated with pharmaceutical or biological agents and polymers, asdescribed in the above embodiments are then subjected to a sinteringprocess. The sintering process takes place under benign conditions,which do not affect the structural and morphological integrity of thepharmaceutical and biological agents, and refers to a process by whichthe co-deposited pharmaceutical agent or biological agent-polymermatrix, becomes continuous and adherent to the substrate. This isachieved by treating the coated substrate with a compressed gas,compressed liquid or supercritical fluid at conditions such that it is apoor solvent of the polymers, a weak solvent of the polymers or anon-solvent for the polymers, the pharmaceutical agents and thebiological agents, but an agent suitable for the treatment of polymerparticles to form continuous polymer coatings. The sintering processtakes place under conditions (e.g. mild temperatures), and using benignfluids (e.g. supercritical carbon dioxide) which will not affect thestructural and morphological integrity of the pharmaceutical andbiological agents. Other sintering processes, which do not affect thestructural and morphological integrity of the pharmaceutical andbiological agents may also be contemplated by the present invention.

In further aspects of the coating process, it is desirable to createcoatings such that release of an active substance occurs with apredetermined elution profile when placed in the desired elution media.Coating properties can be modified in a variety of different ways inorder to provide desirable elution profiles.

The chemical composition of the coating polymers can be varied, toprovide greater or lesser amounts of coating polymers that will allow orrestrict the elution of active substance. For example, if the intendedelution media contain water, a higher content of coating polymers thatswell in water, will allow for a faster elution of active substance.Conversely, a higher content of coating polymers that do not swell inaqueous media will result in a slower elution rate.

The coating properties can also be controlled by alternating coatingpolymer layers. Layers of coating polymers of different properties aredeposited on the substrate in a sequential manner. By modifying thenature of the polymer deposited in each layer (e.g., depositing layersof different polymers) the elution profile of the coating is altered.The number of layers and the sequence in their deposition provideadditional avenues for the design of coatings having controlled elutionprofiles.

The coating properties can also be modified by control of the macroand/or micro-structure of the polymer coating (diffusion pathways). Thismay be achieved by varying the coating process(es) or by using differentsintering conditions.

The coating process provides several approaches for controlling theelution of a drug or several drugs. For example, In some embodiments,controlled elution is achieved by the segregation of different coatingpolymers (e.g. PEVA/PBMA). In another embodiment, control of elution isachieved by controlling the conditions during the sintering process suchthat controlled incomplete sintering of the polymer matrix is obtained,whereby the coating would retain some of the particle-like structure ofthe polymer particles as deposited. Incomplete sintering would providepores/voids in the coating and allow additional pathways for elution ofthe drug, including drug elution around the polymer(s) instead of, or inaddition to, elution through the polymer(s). The size of the pores orvoids obtained through incomplete sintering of the polymer matrix may beobtained through several methods. For example, the rate ofdepressurization of a vessel in which the sintering process is carriedout provides one avenue for controlling pore size. The size of thecavities or pores in the coating can be controlled by employing aporogen as an excipient and subsequent removal of at least a portion ofthe porogen, for example by treatment with a solvent of the porogen.Preferably, the porogen solvent comprises a densified gas (e.g.;carbon). In some embodiments the porogen is an SOA or other suchhydrophobically derivatized carbohydrate. Removal of at least a portionof the porogen is preferably carried out during the sintering process.

In some aspects of the invention, the active substance elution profileis controllable by altering the coating polymer particle size. Themethod by which the polymer particles are deposited onto the substrateis thus varied to provide the desired elution rate. For example, forpolymers released simultaneously through the same nozzle, RESS releasefrom a supercritical solution would typically result in small polymerparticles; RESS-like release from a mixture in a compressed gas usuallygenerates larger polymer particles. Using the SEDS process can result invariable polymer particle size, depending on the particular SEDSconditions employed.

In further aspects of the coating process, the active substance elutionprofile is controllable by altering the coating polymer particle shape.One way to achieve variation in polymer particle shape is to alter theinitial concentration of the polymers. At lower initial concentrations,polymers are deposited as small particles. At increased concentrations,larger particles are formed. At higher concentrations, the formedparticles become elongated, until at high concentrations the elongatedfeatures become fiber-like and eventually become continuous fibers.

In yet other aspects of the coating process, the active substanceelution profile is controllable by creating discrete domains ofchemically different polymers. As described above, chemically differentpolymers will allow or restrict the elution of active substance indifferent elution media. By changing the position of such polymers indiscrete macroscopic domains within the coating, the elution profileswill be adjustable. For example during a process whereby two differentpolymers are released sequentially through the same nozzle, particles ofeither polymer could be deposited to position them, for example, closerto the outside, the inside or the middle of the coating on thesubstrate. In another embodiment, the two polymers may be releasedsimultaneously through two different nozzles at differing and/oralternating deposition rates, resulting in a similar effect. In afurther embodiment, the deposition of eluting and non-eluting polymersis alternated to result in a fluctuating type of release. In yet otherembodiments, the polymers are deposited to provide for a pulsatilerelease of active substance. Separation of the polymer(s) providingdifferent domains for drug diffusion is achieved, for example, bysubsequent spray of the polymers through same nozzle or by usingmultiple nozzles. Also, as described above, controlling the elution ofthe active substance may be achieved by layering of different polymersacross the depth of the coating. A combination of domain separation andcross-depth layering is also contemplated for the design of coatingshaving controlled elution properties.

The deposition of active substance during any of these processes may beconstant to provide even distribution throughout the coating, or thespraying of the active substance may be varied to result in differingamounts of active substance in the differing polymeric domains withinthe coating.

In further aspects of the coating process, the active substance elutionprofile is controllable by varying the coating sintering conditions. Forexample, incomplete sintering will create open spaces, or pores in theinterstitial spaces between the polymer particles, which will enablefaster eluting of active substance from the coating. Another way toutilize the sintering conditions for elution control would be todeliberately create irregular coatings by foaming during the sinteringprocess. Rapid pressure release of a CO₂- or isobutylene-impregnatedpolymer film induces formation of foamed polymers which would create acoating with increased porosity and be very ‘open’ to diffusion/elution.Thus the elution profile would be controllable by manipulating thefoaming conditions, which in turn controls the pore density and size.

Another advantage of the coating process is the ability to create astent with a controlled (dialed-in) drug-elution profile. Via theability to have different materials in each layer of the laminatestructure and the ability to control the location of drug(s)independently in these layers, the method enables a stent that couldrelease drugs at very specific elution profiles, programmed sequentialand/or parallel elution profiles. Also, the present invention allowscontrolled elution of one drug without affecting the elution of a seconddrug (or different doses of the same drug).

The embodiments incorporating a stent form or framework provide theability to radiographically monitor the stent in deployment. In analternative embodiment, the inner-diameter of the stent can be masked(e.g. by a non-conductive mandrel). Such masking would preventadditional layers from being on the interior diameter (abluminal)surface of the stent. The resulting configuration may be desirable toprovide preferential elution of the drug toward the vessel wall (luminalsurface of the stent) where the therapeutic effect of anti-restenosis isdesired, without providing the same antiproliferative drug(s) on theabluminal surface, where they may retard healing, which in turn issuspected to be a cause of late-stage safety problems with current DESs.

The coating process allows for employing a platform combining layerformation methods based on compressed fluid technologies; electrostaticcapture and sintering methods. The platform results in drug elutingstents having enhanced therapeutic and mechanical properties. Thecoating process is particularly advantageous in that it employsoptimized laminate polymer technology. In particular, the coatingprocess allows the formation of discrete layers of specific drugplatforms.

The coating process provided herein the drugs and polymers are coated onthe stent framework in discrete steps, which can be carried outsimultaneously or alternately. This allows discrete deposition of theactive agent (e.g.; a drug) within a polymer matrix thereby allowing theplacement of more than one drug on a single medical device with orwithout an intervening polymer layer. For example, the present platformprovides a dual drug eluting stent.

Some of the advantages provided by the coating process include employingcompressed fluids (e.g., supercritical fluids, for example RESS basedmethods); solvent free deposition methodology; a platform that allowsprocessing at lower temperatures thereby preserving the qualities of theactive agent and the polymer matrix; the ability to incorporate two,three or more drugs while minimizing deleterious effects from directinteractions between the various drugs and/or their excipients duringthe fabrication and/or storage of the drug eluting stents; a drydeposition; enhanced adhesion and mechanical properties of the layers onthe stent framework; precision deposition and rapid batch processing;and ability to form intricate structures.

The coating process may provide a multi-drug delivery platform whichproduces strong, resilient and flexible drug eluting stents including ananti-restenosis drug (e.g.; a limus or taxol) and anti-thrombosis drug(e.g.; heparin or an analog thereof) and well characterizedbioabsorbable polymers. The drug eluting stents provided herein minimizepotential for thrombosis, in part, by reducing or totally eliminatingthrombogenic polymers and reducing or totally eliminating residual drugsthat could inhibit healing.

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The terms “bioabsorbable,” “biodegradable,” “bioerodible,”“bioresorbable,” and “resorbable” are art-recognized synonyms. Theseterms are used herein interchangeably. Bioabsorbable polymers typicallydiffer from non-bioabsorbable polymers in that the former may beabsorbed (e.g.; degraded) during use. In certain embodiments, such useinvolves in vivo use, such as in vivo therapy, and in other certainembodiments, such use involves in vitro use. In general, degradationattributable to biodegradability involves the degradation of abioabsorbable polymer into its component subunits, or digestion, e.g.,by a biochemical process, of the polymer into smaller, non-polymericsubunits. In certain embodiments, biodegradation may occur by enzymaticmediation, degradation in the presence of water (hydrolysis) and/orother chemical species in the body, or both. The bioabsorbability of apolymer may be indicated in-vitro as described herein or by methodsknown to one of skill in the art. An in-vitro test for bioabsorbabilityof a polymer does not require living cells or other biologic materialsto indicate bioabsorption properties (e.g. degradation, digestion).Thus, resorbtion, resorption, absorption, absorbtion, erosion may alsobe used synonymously with the terms “bioabsorbable,” “biodegradable,”“bioerodible,” and “bioresorbable.” Mechanisms of degradation of abioabsorbable polymer may include, but are not limited to, bulkdegradation, surface erosion, and combinations thereof.

As used herein, the term “biodegradation” encompasses both general typesof biodegradation. The degradation rate of a biodegradable polymer oftendepends in part on a variety of factors, including the chemical identityof the linkage responsible for any degradation, the molecular weight,crystallinity, biostability, and degree of cross-linking of suchpolymer, the physical characteristics (e.g., shape and size) of theimplant, and the mode and location of administration. For example, thegreater the molecular weight, the higher the degree of crystallinity,and/or the greater the biostability, the biodegradation of anybioabsorbable polymer is usually slower.

“Degradation” as used herein refers to the conversion or reduction of achemical compound to one less complex, e.g., by splitting off one ormore groups of atoms. Degradation of the coating may reduce thecoating's cohesive and adhesive binding to the device, therebyfacilitating transfer of the coating to the intervention site

“Pharmaceutical agent” as used herein refers to any of a variety ofdrugs or pharmaceutical compounds that can be used as active agents toprevent or treat a disease (meaning any treatment of a disease in amammal, including preventing the disease, i.e. causing the clinicalsymptoms of the disease not to develop; inhibiting the disease, i.e.arresting the development of clinical symptoms; and/or relieving thedisease, i.e. causing the regression of clinical symptoms). It ispossible that the pharmaceutical agents of the invention may alsocomprise two or more drugs or pharmaceutical compounds. Pharmaceuticalagents, include but are not limited to antirestenotic agents,antidiabetics, analgesics, antiinflammatory agents, antirheumatics,antihypotensive agents, antihypertensive agents, psychoactive drugs,tranquilizers, antiemetics, muscle relaxants, glucocorticoids, agentsfor treating ulcerative colitis or Crohn's disease, antiallergics,antibiotics, antiepileptics, anticoagulants, antimycotics, antitussives,arteriosclerosis remedies, diuretics, proteins, peptides, enzymes,enzyme inhibitors, gout remedies, hormones and inhibitors thereof,cardiac glycosides, immunotherapeutic agents and cytokines, laxatives,lipid-lowering agents, migraine remedies, mineral products, otologicals,anti parkinson agents, thyroid therapeutic agents, spasmolytics,platelet aggregation inhibitors, vitamins, cytostatics and metastasisinhibitors, phytopharmaceuticals, chemotherapeutic agents and aminoacids. Examples of suitable active ingredients are acarbose, antigens,beta-receptor blockers, non-steroidal antiinflammatory drugs [NSAIDs],cardiac glycosides, acetylsalicylic acid, virustatics, aclarubicin,acyclovir, cisplatin, actinomycin, alpha- and beta-sympatomimetics,(dmeprazole, allopurinol, alprostadil, prostaglandins, amantadine,ambroxol, amlodipine, methotrexate, S-aminosalicylic acid,amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine,balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide,diazepam and diazepam derivatives, budesonide, bufexamac, buprenorphine,methadone, calcium salts, potassium salts, magnesium salts, candesartan,carbamazepine, captopril, cefalosporins, cetirizine, chenodeoxycholicacid, ursodeoxycholic acid, theophylline and theophylline derivatives,trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin,clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D andderivatives of vitamin D, colestyramine, cromoglicic acid, coumarin andcoumarin derivatives, cysteine, cytarabine, cyclophosphamide,ciclosporin, cyproterone, cytabarine, dapiprazole, desogestrel,desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate,dimethyl sulphoxide, dimeticone, domperidone and domperidan derivatives,dopamine, doxazosin, doxorubizin, doxylamine, dapiprazole,benzodiazepines, diclofenac, glycoside antibiotics, desipramine,econazole, ACE inhibitors, enalapril, ephedrine, epinephrine, epoetinand epoetin derivatives, morphinans, calcium antagonists, irinotecan,modafinil, orlistat, peptide antibiotics, phenytoin, riluzoles,risedronate, sildenafil, topiramate, macrolide antibiotics, oestrogenand oestrogen derivatives, progestogen and progestogen derivatives,testosterone and testosterone derivatives, androgen and androgenderivatives, ethenzamide, etofenamate, etofibrate, fenofibrate,etofylline, etoposide, famciclovir, famotidine, felodipine, fenofibrate,fentanyl, fenticonazole, gyrase inhibitors, fluconazole, fludarabine,fluarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen,flutamide, fluvastatin, follitropin, formoterol, fosfomicin, furosemide,fusidic acid, gallopamil, ganciclovir, gemfibrozil, gentamicin, ginkgo,Saint John's wort, glibenclamide, urea derivatives as oralantidiabetics, glucagon, glucosamine and glucosamine derivatives,glutathione, glycerol and glycerol derivatives, hypothalamus hormones,goserelin, gyrase inhibitors, guanethidine, halofantrine, haloperidol,heparin and heparin derivatives, hyaluronic acid, hydralazine,hydrochlorothiazide and hydrochlorothiazide derivatives, salicylates,hydroxyzine, idarubicin, ifosfamide, imipramine, indometacin,indoramine, insulin, interferons, iodine and iodine derivatives,isoconazole, isoprenaline, glucitol and glucitol derivatives,itraconazole, ketoconazole, ketoprofen, ketotifen, lacidipine,lansoprazole, levodopa, levomethadone, thyroid hormones, lipoic acid andlipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine,loperamide, loratadine, maprotiline, mebendazole, mebeverine, meclozine,mefenamic acid, mefloquine, meloxicam, mepindolol, meprobamate,meropenem, mesalazine, mesuximide, metamizole, metformin, methotrexate,methylphenidate, methylprednisolone, metixene, metoclopramide,metoprolol, metronidazole, mianserin, miconazole, minocycline,minoxidil, misoprostol, mitomycin, mizolastine, moexipril, morphine andmorphine derivatives, evening primrose, nalbuphine, naloxone, tilidine,naproxen, narcotine, natamycin, neostigmine, nicergoline, nicethamide,nifedipine, niflumic acid, nimodipine, nimorazole, nimustine,nisoldipine, adrenaline and adrenaline derivatives, norfloxacin,novamine sulfone, noscapine, nystatin, ofloxacin, olanzapine,olsalazine, omeprazole, omoconazole, ondansetron, oxaceprol, oxacillin,oxiconazole, oxymetazoline, pantoprazole, paracetamol, paroxetine,penciclovir, oral penicillins, pentazocine, pentifylline,pentoxifylline, perphenazine, pethidine, plant extracts, phenazone,pheniramine, barbituric acid derivatives, phenylbutazone, phenytoin,pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil,piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine,propiverine, propranolol, propyphenazone, prostaglandins, protionamide,proxyphylline, quetiapine, quinapril, quinaprilat, ramipril, ranitidine,reproterol, reserpine, ribavirin, rifampicin, risperidone, ritonavir,ropinirole, roxatidine, roxithromycin, ruscogenin, rutoside and rutosidederivatives, sabadilla, salbutamol, salmeterol, scopolamine, selegiline,sertaconazole, sertindole, sertralion, silicates, sildenafil,simvastatin, sitosterol, sotalol, spaglumic acid, sparfloxacin,spectinomycin, spiramycin, spirapril, spironolactone, stavudine,streptomycin, sucralfate, sufentanil, sulbactam, sulphonamides,sulfasalazine, sulpiride, sultamicillin, sultiam, sumatriptan,suxamethonium chloride, tacrine, tacrolimus, taliolol, tamoxifen,taurolidine, tazarotene, temazepam, teniposide, tenoxicam, terazosin,terbinafine, terbutaline, terfenadine, terlipressin, tertatolol,tetracycline, teryzoline, theobromine, theophylline, butizine,thiamazole, phenothiazines, thiotepa, tiagabine, tiapride, propionicacid derivatives, ticlopidine, timolol, tinidazole, tioconazole,tioguanine, tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide,tolcapone, tolnaftate, tolperisone, topotecan, torasemide,antioestrogens, tramadol, tramazoline, trandolapril, tranylcypromine,trapidil, trazodone, triamcinolone and triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine,tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol,tropalpin, troxerutine, tulobuterol, tyramine, tyrothricin, urapidil,ursodeoxycholic acid, chenodeoxycholic acid, valaciclovir, valproicacid, vancomycin, vecuronium chloride, Viagra, venlafaxine, verapamil,vidarabine, vigabatrin, viloazine, vinblastine, vincamine, vincristine,vindesine, vinorelbine, vinpocetine, viquidil, warfarin, xantinolnicotinate, xipamide, zafirlukast, zalcitabine, zidovudine,zolmitriptan, zolpidem, zoplicone, zotipine and the like. See, e.g.,U.S. Pat. No. 6,897,205; see also U.S. Pat. No. 6,838,528; U.S. Pat. No.6,497,729.

Examples of therapeutic agents employed in conjunction with theinvention include, rapamycin, 40-O-(2-Hydroxyethyl)rapamycin(everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4'S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin,40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin,40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin,40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin,40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

The active ingredients may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives (meaning saltswhich retain the biological effectiveness and properties of thecompounds of this invention and which are not biologically or otherwiseundesirable), and in the case of chiral active ingredients it ispossible to employ both optically active isomers and racemates ormixtures of diastereoisomers.

“Stability” as used herein in refers to the stability of the drug in apolymer coating deposited on a substrate in its final product form(e.g., stability of the drug in a coated stent). The term stability willdefine 5% or less degradation of the drug in the final product form.

“Active biological agent” as used herein refers to a substance,originally produced by living organisms, that can be used to prevent ortreat a disease (meaning any treatment of a disease in a mammal,including preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop; inhibiting the disease, i.e. arresting thedevelopment of clinical symptoms; and/or relieving the disease, i.e.causing the regression of clinical symptoms). It is possible that theactive biological agents of the invention may also comprise two or moreactive biological agents or an active biological agent combined with apharmaceutical agent, a stabilizing agent or chemical or biologicalentity. Although the active biological agent may have been originallyproduced by living organisms, those of the present invention may alsohave been synthetically prepared, or by methods combining biologicalisolation and synthetic modification. By way of a non-limiting example,a nucleic acid could be isolated form from a biological source, orprepared by traditional techniques, known to those skilled in the art ofnucleic acid synthesis. Furthermore, the nucleic acid may be furthermodified to contain non-naturally occurring moieties. Non-limitingexamples of active biological agents include peptides, proteins,enzymes, glycoproteins, nucleic acids (including deoxyribonucleotide orribonucleotide polymers in either single or double stranded form, andunless otherwise limited, encompasses known analogues of naturalnucleotides that hybridize to nucleic acids in a manner similar tonaturally occurring nucleotides), antisense nucleic acids, fatty acids,antimicrobials, vitamins, hormones, steroids, lipids, polysaccharides,carbohydrates and the like. They further include, but are not limitedto, antirestenotic agents, antidiabetics, analgesics, antiinflammatoryagents, antirheumatics, antihypotensive agents, antihypertensive agents,psychoactive drugs, tranquilizers, antiemetics, muscle relaxants,glucocorticoids, agents for treating ulcerative colitis or Crohn'sdisease, antiallergics, antibiotics, antiepileptics, anticoagulants,antimycotics, antitussives, arteriosclerosis remedies, diuretics,proteins, peptides, enzymes, enzyme inhibitors, gout remedies, hormonesand inhibitors thereof, cardiac glycosides, immunotherapeutic agents andcytokines, laxatives, lipid-lowering agents, migraine remedies, mineralproducts, otologicals, anti parkinson agents, thyroid therapeuticagents, spasmolytics, platelet aggregation inhibitors, vitamins,cytostatics and metastasis inhibitors, phytopharmaceuticals andchemotherapeutic agents. Preferably, the active biological agent is apeptide, protein or enzyme, including derivatives and analogs of naturalpeptides, proteins and enzymes.

“Activity” as used herein refers to the ability of a pharmaceutical oractive biological agent to prevent or treat a disease (meaning anytreatment of a disease in a mammal, including preventing the disease,i.e. causing the clinical symptoms of the disease not to develop;inhibiting the disease, i.e. arresting the development of clinicalsymptoms; and/or relieving the disease, i.e. causing the regression ofclinical symptoms). Thus the activity of a pharmaceutical or activebiological agent should be of therapeutic or prophylactic value.

“Secondary, tertiary and quaternary structure” as used herein aredefined as follows. The active biological agents of the presentinvention will typically possess some degree of secondary, tertiaryand/or quaternary structure, upon which the activity of the agentdepends. As an illustrative, non-limiting example, proteins possesssecondary, tertiary and quaternary structure. Secondary structure refersto the spatial arrangement of amino acid residues that are near oneanother in the linear sequence. The α-helix and the β-strand areelements of secondary structure. Tertiary structure refers to thespatial arrangement of amino acid residues that are far apart in thelinear sequence and to the pattern of disulfide bonds. Proteinscontaining more than one polypeptide chain exhibit an additional levelof structural organization. Each polypeptide chain in such a protein iscalled a subunit. Quaternary structure refers to the spatial arrangementof subunits and the nature of their contacts. For example hemoglobinconsists of two α and two β chains. It is well known that proteinfunction arises from its conformation or three dimensional arrangementof atoms (a stretched out polypeptide chain is devoid of activity). Thusone aspect of the present invention is to manipulate active biologicalagents, while being careful to maintain their conformation, so as not tolose their therapeutic activity.

“Polymer” as used herein, refers to a series of repeating monomericunits that have been cross-linked or polymerized. Any suitable polymercan be used to carry out the present invention. It is possible that thepolymers of the invention may also comprise two, three, four or moredifferent polymers. In some embodiments, of the invention only onepolymer is used. In some preferred embodiments a combination of twopolymers are used. Combinations of polymers can be in varying ratios, toprovide coatings with differing properties. Those of skill in the art ofpolymer chemistry will be familiar with the different properties ofpolymeric compounds. Examples of polymers that may be used in thepresent invention include, but are not limited to polycarboxylic acids,cellulosic polymers, proteins, polypeptides, polyvinylpyrrolidone,maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethyleneoxides, glycosaminoglycans, polysaccharides, polyesters, polyurethanes,polystyrenes, copolymers, silicones, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropylenes, polylactic acids, polyglycolic acids, polycaprolactones,polyhydroxybutyrate valerates, polyacrylamides, polyethers, polyurethanedispersions, polyacrylates, acrylic latex dispersions, polyacrylic acid,mixtures and copolymers thereof. The polymers of the present inventionmay be natural or synthetic in origin, including gelatin, chitosan,dextrin, cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as poly(methyl methacrylate), poly(butylmethacrylate), and Poly(2-hydroxy ethyl methacrylate), Poly(vinylalcohol) Poly(olefins) such as poly(ethylene), poly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)- and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid);etc. Suitable polymers also include absorbable and/or resorbablepolymers including the following, combinations, copolymers andderivatives of the following: Polylactides (PLA), Polyglycolides (PGA),Poly(lactide-co-glycolides) (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(l-aspartamide), etc.

“Therapeutically desirable morphology” as used herein refers to thegross form and structure of the pharmaceutical agent, once deposited onthe substrate, so as to provide for optimal conditions of ex vivostorage, in vivo preservation and/or in vivo release. Such optimalconditions may include, but are not limited to increased shelf life,increased in vivo stability, good biocompatibility, good bioavailabilityor modified release rates. Typically, for the present invention, thedesired morphology of a pharmaceutical agent would be crystalline orsemi-crystalline or amorphous, although this may vary widely dependingon many factors including, but not limited to, the nature of thepharmaceutical agent, the disease to be treated/prevented, the intendedstorage conditions for the substrate prior to use or the location withinthe body of any biomedical implant. Preferably at least 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90% or 100% of the pharmaceutical agent is incrystalline or semi-crystalline form.

“Stabilizing agent” as used herein refers to any substance thatmaintains or enhances the stability of the biological agent. Ideallythese stabilizing agents are classified as Generally Regarded As Safe(GRAS) materials by the US Food and Drug Administration (FDA). Examplesof stabilizing agents include, but are not limited to carrier proteins,such as albumin, gelatin, metals or inorganic salts. Pharmaceuticallyacceptable excipient that may be present can further be found in therelevant literature, for example in the Handbook of PharmaceuticalAdditives: An International Guide to More Than 6000 Products by TradeName, Chemical, Function, and Manufacturer; Michael and Irene Ash(Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

“Compressed fluid” as used herein refers to a fluid of appreciabledensity (e.g., >0.2 g/cc) that is a gas at standard temperature andpressure. “Supercritical fluid”, “near-critical fluid”,“near-supercritical fluid”, “critical fluid”, “densified fluid” or“densified gas” as used herein refers to a compressed fluid underconditions wherein the temperature is at least 80% of the criticaltemperature of the fluid and the pressure is at least 50% of thecritical pressure of the fluid.

Examples of substances that demonstrate supercritical or near criticalbehavior suitable for the present invention include, but are not limitedto carbon dioxide, isobutylene, ammonia, water, methanol, ethanol,ethane, propane, butane, pentane, dimethyl ether, xenon, sulfurhexafluoride, halogenated and partially halogenated materials such aschlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons,perfluorocarbons (such as perfluoromethane and perfuoropropane,chloroform, trichloro-fluoromethane, dichloro-difluoromethane,dichloro-tetrafluoroethane) and mixtures thereof.

“Sintering” as used herein refers to the process by which parts of thematrix or the entire polymer matrix becomes continuous (e.g., formationof a continuous polymer film). As discussed below, the sintering processis controlled to produce a fully conformal continuous matrix (completesintering) or to produce regions or domains of continuous coating whileproducing voids (discontinuities) in the matrix. As well, the sinteringprocess is controlled such that some phase separation is obtainedbetween polymer different polymers (e.g., polymers A and B) and/or toproduce phase separation between discrete polymer particles. Through thesintering process, the adhesions properties of the coating are improvedto reduce flaking of detachment of the coating from the substrate duringmanipulation in use. As described below, in some embodiments, thesintering process is controlled to provide incomplete sintering of thepolymer matrix. In embodiments involving incomplete sintering, a polymermatrix is formed with continuous domains, and voids, gaps, cavities,pores, channels or, interstices that provide space for sequestering atherapeutic agent which is released under controlled conditions.Depending on the nature of the polymer, the size of polymer particlesand/or other polymer properties, a compressed gas, a densified gas, anear critical fluid or a super-critical fluid may be employed. In oneexample, carbon dioxide is used to treat a substrate that has beencoated with a polymer and a drug, using dry powder and RESSelectrostatic coating processes. In another example, isobutylene isemployed in the sintering process. In other examples a mixture of carbondioxide and isobutylene is employed.

When an amorphous material is heated to a temperature above its glasstransition temperature, or when a crystalline material is heated to atemperature above a phase transition temperature, the moleculescomprising the material are more mobile, which in turn means that theyare more active and thus more prone to reactions such as oxidation.However, when an amorphous material is maintained at a temperature belowits glass transition temperature, its molecules are substantiallyimmobilized and thus less prone to reactions. Likewise, when acrystalline material is maintained at a temperature below its phasetransition temperature, its molecules are substantially immobilized andthus less prone to reactions. Accordingly, processing drug components atmild conditions, such as the deposition and sintering conditionsdescribed herein, minimizes cross-reactions and degradation of the drugcomponent. One type of reaction that is minimized by the processes ofthe invention relates to the ability to avoid conventional solventswhich in turn minimizes autoxidation of drug, whether in amorphous,semi-crystalline, or crystalline form, by reducing exposure thereof tofree radicals, residual solvents and autoxidation initiators.

“Rapid Expansion of Supercritical Solutions” or “RESS” as used hereininvolves the dissolution of a polymer into a compressed fluid, typicallya supercritical fluid, followed by rapid expansion into a chamber atlower pressure, typically near atmospheric conditions. The rapidexpansion of the supercritical fluid solution through a small opening,with its accompanying decrease in density, reduces the dissolutioncapacity of the fluid and results in the nucleation and growth ofpolymer particles. The atmosphere of the chamber is maintained in anelectrically neutral state by maintaining an isolating “cloud” of gas inthe chamber. Carbon dioxide or other appropriate gas is employed toprevent electrical charge is transferred from the substrate to thesurrounding environment.

“Bulk properties” properties of a coating including a pharmaceutical ora biological agent that can be enhanced through the methods of theinvention include for example: adhesion, smoothness, conformality,thickness, and compositional mixing.

The present invention provides several advantages which overcome orattenuate the limitations of current technology for bioabsorbablestents. Fro example, an inherent limitation of conventionalbioabsorbable polymeric materials relates to the difficulty in formingto a strong, flexible, deformable (e.g. balloon deployable) stent withlow profile. The polymers generally lack the strength ofhigh-performance metals. The present invention overcomes theselimitations by creating a laminate structure in the essentiallypolymeric stent. Without wishing to be bound by any specific theory oranalogy, the increased strength provided by the stents of the inventioncan be understood by comparing the strength of plywood vs. the strengthof a thin sheet of wood.

Embodiments of the invention involving a thin metallic stent-frameworkprovide advantages including the ability to overcome the inherentelasticity of most polymers. It is generally difficult to obtain a highrate (e.g., 100%) of plastic deformation in polymers (compared toelastic deformation where the materials have some ‘spring back’ to theoriginal shape). Again, without wishing to be bound by any theory, thecentral metal stent ramework (that would be too small and weak to serveas a stent itself) would act like wires inside of a plastic, deformablestent, basically overcoming any ‘elastic memory’ of the polymer.

EXAMPLES

The following examples are given to enable those skilled in the art tomore clearly understand and to practice the present invention. Theyshould not be considered as limiting the scope of the invention, butmerely as being illustrative and representative thereof. The followingexamples are provided to illustrate selected embodiments. They shouldnot be considered as limiting the scope of the invention, but merely asbeing illustrative and representative thereof. Thus, the examplesprovided below, while illustrated with a particular medical device oractive agent, are applicable to the range of medical devices and activeagents described herein.

Polymer Stent Example 1 Bioabsorbable Stent Formed from Polymer Tube

In a non-limiting example, the tubular scaffold is made by laser-cuttinga stent design from the polymer tube. In some embodiments, the stentdesign is cut from the polymer tube using a polymer-compatible laser,such as carbon dioxide laser beam or other suitable laser cuttingtechnologies in light of the present disclosure. In another embodiment,the stent design is cut from the polymer tube by water jet cutting orabrasive water jet cutting. Alternatively, the tubular scaffold can bemade through photochemical etching or chemical etching. Many slottedtube stent designs can be used to make the bioabsorbable stentsdisclosed herein. For example, suitable stent deigns may include, butare not limited to, bStent2 by Medtronic; BiodivYsio by BiocompatiblesLtd.; Velocity, Palmaz-Schatz 153/154, Palmaz-Schatz Crown by Cordis;Express by Boston Scientific; JOSTENT Flex by JOMED; Multi-Link PENTA,Multi-Link Rx, and Multi-Link Vision by Guidant; and NIR and NIR Flex byMedinol. Other stent designs may also be used in light of the presentdisclosure.

Example 2 Bioabsorbable Stent Formed from Polymer Fibers

In a non-limiting example, the tubular scaffold of the presentdisclosure is made by forming a continuous wave form that includes aplurality of struts and a plurality of crowns. Each crown is a curvedportion or turn within the wave form that connects adjacent struts todefine the continuous wave form. In this example, the struts aresubstantially straight portions of the wave form. In other examples, thestruts are slightly bent or have other shapes, such as a sinusoidalwave, for example. The wave form may be formed by a single polymer fiberor filament or a plurality of interconnected polymer fibers orfilaments.

After the wave form is formed, the wave form is wrapped around amandrel, a center axis of which defines the longitudinal axis of thetubular scaffold. The wave form may be wrapped at an angle that is notperpendicular to the longitudinal axis to form a plurality of helicalturns that together generally form a helical coil in the shape of ahelix.

The tubular scaffold also includes a plurality of connections that areconfigured to connect selected crowns of adjacent turns. In someembodiments, the tubular scaffold includes three connections percomplete helix turn. In some embodiments, the tubular scaffold includesfour connections per complete helix turn. In some embodiments, thetubular scaffold includes five connections per complete helix turn.Other connection numbers and configurations can also be used in light ofthe present disclosure. In a non-limiting example, the connections arecreated by fusing the selected crowns together. As used herein, “fusing”is defined as heating the target portions of materials to be fusedtogether, with or without adding any additional material, to a levelwhere the material in the target portions flow together, intermix withone another, and form a fusion when the materials cool down to, forexample, room temperature.

Many methods for forming wire- or filament-based stents can be used tomake the bioabsorbable stents disclosed herein. For example, the methodsfor forming Wallstent (Boston Scientific), S7 (Medtronic), AngioStent(AngioDynamics), Strecker (Boston Scientific), Expander (Medicorp),Horizon Prostatic (Endocare), Endocoil (InStent), etc, can be used to inlight of the present disclosure.

Example 3 Radial Strength Testing

This test is conducted to determine and graphically represent the changein stent internal diameter as a function of circumferential pressure andto determine the pressure at which deformation is no longer completelyreversible for the disclosed stent. Fifteen (15) 3.0 mm and fifteen (15)4.0 mm stents are subjected to all stent-manufacturing procedures. Thestents are deployed to nominal pressure and removed from the deliverysystem. The stents are placed into a sleeve approximately lmm largerthan the stent diameter. A vacuum is then applied and outer diametermeasurements taken at various pressures. All samples should maintain aminimum of at least 50 percent of the nominal stent diameter after a 50mm Hg pressure is applied.

Example 4 Stent Recoil Testing

This test is conducted to quantify the amount of elastic recoil. Fifteen(15) stent delivery systems of each length and diameter are subjected toall manufacturing and sterilization procedures. The stent deliverysystem is inflated to nominal pressure (e.g. 9 ATM) and the stent isremoved allowing for recoil to occur. The inner diameter at each end ofthe stent is recorded. Recoil is calculated subtracting the recoiledstent inner diameter from the pre-recoil inner diameter. Average recoilmay ranged from 0.002 to 0.004 inches.

Example 5 Stent Expansion Testing

This test is conducted to determine if the plastic deformationexperienced by the stent when expanded from the compressed profile tothe final maximum deployed diameter can produce crack initiation for thedisclosed stent. Fifteen (15) samples from each length and diameter aredeployed to their largest possible diameters by inflating each deliverysystem to balloon failure. Each stent is examined at 45× magnificationfor potential cracks.

Example 6 Maximum Pressure (Burst Test) Testing

This test is conducted to demonstrate that the delivery system (withmounted stent) will not experience balloon, shaft, proximal adaptationor proximal/distal seal loss of integrity at or below the pressurerequired to expand the stent to its labeled diameter. Stent deliverysystems that had been subjected to all manufacturing and sterilizationprocedures are pressurized to 90 psi with pressure held for 15 secondsand released for 3 seconds. The cycle is then repeated, increasinginflation pressure by 15 psi each cycle until failure.

Example 7 Analysis of the Strut Thickness Scanning Electron Microscopy(SEM)

A sample coated stent described herein is obtained. Thickness of thedevice can be assessed using this analytical technique. The thickness ofmultiple struts were taken to ensure reproducibility and to characterizethe coating and stent. The thickness of the coating was observed by SEMusing a Hitachi 5-4800 with an accelerating voltage of 800V. Variousmagnifications are used. SEM can provide top-down and cross-sectionimages at various magnifications.

Nano X-Ray Computer Tomography

Another technique that may be used to view the physical structure of adevice in 3-D is Nano X-Ray Computer Tomography (e.g. such as made bySkyScan).

Example 8 Determination of the Bioabsorbability of a Device

Techniques presented with respect to showing Bioabsorbability of apolymer coating may be used to additionally and/or alternatively showthe bioabsorbability of a device, for example, by GPC In-Vivo testing,HPLC In-Vivo Testing, GPC In-Vitro testing, HPLC In-Vitro Testing,SEM-FIB Testing, Raman Spectroscopy, SEM, and XPS as described hereinwith variations and adjustments which would be obvious to those skilledin the art. Another technique to view the physical structure of a devicein 3-D is Nano X-Ray Computer Tomography (e.g. such as made by SkyScan),which could be used in an elution test and/or bioabsorbability test, asdescribed herein to show the physical structure of the coating remainingon stents at each time point, as compared to a scan prior toelution/bioabsorbtion.

Drug Elution Polymer Stent Example 11 Determination of an ElutionProfile In Vitro

In one method, a stent described herein is obtained. The elution profileis determined as follows: stents are placed in 16 mL test tubes and 15mL of 10 mM PBS (pH 7.4) is pipetted on top. The tubes are capped andincubated at 37 C with end-over-end rotation at 8 rpm. Solutions arethen collected at the designated time points (e.g. 1 d, 7 d, 14 d, 21 d,and 28 d) (e.g. 1 week, 2 weeks, and 10 weeks) and replenished withfresh 1.5 ml solutions at each time point to prevent saturation. One mLof DCM is added to the collected sample of buffer and the tubes arecapped and shaken for one minute and then centrifuged at 200.times.G for2 minutes. The supernatant is discarded and the DCM phase is evaporatedto dryness under gentle heat (40.degree. C.) and nitrogen gas. The driedDCM is reconstituted in 1 mL of 60:40 acetonitrile:water (v/v) andanalyzed by HPLC. HPLC analysis is performed using Waters HPLC system(mobile phase 58:37:5 acetonitrile:water:methanol 1 mL/min, 20 uLinjection, C18 Novapak Waters column with detection at 232 nm).

In another method, the in vitro pharmaceutical agent elution profile isdetermined by a procedure comprising contacting the device with anelution media comprising ethanol (5%) wherein the pH of the media isabout 7.4 and wherein the device is contacted with the elution media ata temperature of about 37.degree. C. The elution media containing thedevice is optionally agitating the elution media during the contactingstep. The device is removed (and/or the elution media is removed) atleast at designated time points (e.g. 1 h, 3 h, 5 h, 7 h, 1 d, and dailyup to 28 d) (e.g. 1 week, 2 weeks, and 10 weeks). The elution media isthen assayed using a UV-Vis for determination of the pharmaceuticalagent content. The elution media is replaced at each time point withfresh elution media to avoid saturation of the elution media.Calibration standards containing known amounts of drug were also held inelution media for the same durations as the samples and used at eachtime point to determine the amount of drug eluted at that time (inabsolute amount and as a cumulative amount eluted).

In another method, the in vitro pharmaceutical agent elution profile isdetermined by a procedure comprising contacting the device with anelution media comprising ethanol (20%) and phosphate buffered saline(80%) wherein the pH of the media is about 7.4 and wherein the device iscontacted with the elution media at a temperature of about 37.degree. C.The elution media containing the device is optionally agitating theelution media during the contacting step. The device is removed (and/orthe elution media is removed) at least at designated time points (e.g. 1h, 3 h, 5 h, 7 h, 1 d, and daily up to 28 d) (e.g. 1 week, 2 weeks, and10 weeks). The elution media is replaced periodically (at least at eachtime point, and/or daily between later time points) to preventsaturation; the collected media are pooled together for each time point.The elution media is then assayed for determination of thepharmaceutical agent content using HPLC. The elution media is replacedat each time point with fresh elution media to avoid saturation of theelution media. Calibration standards containing known amounts of drugare also held in elution media for the same durations as the samples andused at each time point to determine the amount of drug eluted at thattime (in absolute amount and as a cumulative amount eluted). Where theelution method changes the drug over time, resulting in multiple peakspresent for the drug when tested, the use of these calibration standardswill also show this change, and allows for adding all the peaks to givethe amount of drug eluted at that time period (in absolute amount and asa cumulative amount eluted).

To obtain an accelerated in-vitro elution profile, an acceleratedelution buffer comprising 18% v/v of a stock solution of 0.067 mol/LKH₂PO₄ and 82% v/v of a stock solution of 0.067 mol/L Na2HPO4 with a pHof 7.4 is used. Stents described herein are expanded and then placed in1.5 ml solution of this accelerated elution in a 70 degree Celsius bathwith rotation at 70 rpm. The solutions are then collected at thefollowing time points: 0 min., 15 min., 30 min., 1 hr, 2 hr, 4 hr, 6 hr,8 hr, 12 hr, 16 hr, 20 hr, 24 hr, 30 hr, 36 hr and 48 hr. Freshaccelerated elution buffer are added periodically at least at each timepoint to replace the incubated buffers that are collected and saved inorder to prevent saturation. For time points where multiple elutionmedia are used (refreshed between time points), the multiple collectedsolutions are pooled together for liquid extraction by dichloromethane.Dichloromethane extraction and HPLC analysis is performed in the mannerdescribed previously.

In Vivo

Rabbit in vivo models as described above are euthanized at multiple timepoints. Stents are explanted from the rabbits. The explanted stents areplaced in 16 mL test tubes and 15 mL of 10 mM PBS (pH 7.4) is pipette ontop. One mL of DCM is added to the buffer and the tubes are capped andshaken for one minute and then centrifuged at 200.times.G for 2 minutes.The supernatant is discarded and the DCM phase is evaporated to drynessunder gentle heat (40.degree. C.) and nitrogen gas. The dried DCM isreconstituted in 1 mL of 60:40 acetonitrile:water (v/v) and analyzed byHPLC. HPLC analysis is performed using Waters HPLC system (mobile phase58:37:5 acetonitrile:water:methanol 1 mL/min, 20 uL injection, C18Novapak Waters column with detection at 232 nm).

Example 12 Crystallinity of Drug

The presence and or quantification of the active agent crystallinity canbe determined from a number of characterization methods known in theart, but not limited to, XRPD, vibrational spectroscopy (FTIR, NIR,Raman), polarized optical microscopy, calorimetry, thermal analysis andsolid-state NMR.

X-Ray Diffraction to Determine the Presence and/or Quantification ofActive Agent Crystallinity

Active agent and polymer coated proxy substrates are prepared using 316Lstainless steel coupons for X-ray powder diffraction (XRPD) measurementsto determine the presence of crystallinity of the active agent. Thecoating on the coupons is equivalent to the coating on the stentsdescribed herein. Coupons of other materials described herein, such ascobalt-chromium alloys, may be similarly prepared and tested. Likewise,substrates such as stents, or other medical devices described herein maybe prepared and tested. Where a coated stent is tested, the stent may becut lengthwise and opened to lay flat in a sample holder.

For example XRPD analyses are performed using an X-ray powderdiffractometer (for example, a Bruker D8 Advance X-ray diffractometer)using Cu Kα radiation. Diffractograms are typically collected between 2and 40 degrees 2 theta. Where required low background XRPD sampleholders are employed to minimize background noise.

The diffractograms of the deposited active agent are compared withdiffractograms of known crystallized active agents, for examplemicronized crystalline sirolimus in powder form. XRPD patterns ofcrystalline forms show strong diffraction peaks whereas amorphous showdiffuse and non-distinct patterns. Crystallinity is shown in arbitraryIntensity units.

A related analytical technique which may also be used to providecrystallinity detection is wide angle scattering of radiation (e.g.;Wide Anle X-ray Scattering or WAXS), for example, as described in F.Unger, et al., “Poly(ethylene carbonate): A thermoelastic andbiodegradable biomaterial for drug eluting stent coatings?” Journal ofControlled Release, Volume 117, Issue 3, 312-321 (2007) for which thetechnique and variations of the technique specific to a particularsample would be obvious to one of skill in the art.

Raman Spectroscopy

Raman spectroscopy, a vibrational spectroscopy technique, can be useful,for example, in chemical identification, characterization of molecularstructures, effects of bonding, identification of solid state form,environment and stress on a sample. Raman spectra can be collected froma very small volume (<1 μm³); these spectra allow the identification ofspecies present in that volume. Spatially resolved chemical information,by mapping or imaging, terms often used interchangeably, can be achievedby Raman microscopy.

Raman spectroscopy and other analytical techniques such as described inBalss, et al., “Quantitative spatial distribution of sirolimus andpolymers in drug-eluting stents using confocal Raman microscopy” J. ofBiomedical Materials Research Part A, 258-270 (2007), incorporated inits entirety herein by reference, and/or described in Belu et al.,“Three-Dimensional Compositional Analysis of Drug Eluting Stent CoatingsUsing Cluster Secondary Ion Mass Spectroscopy” Anal. Chem. 80: 624-632(2008) incorporated herein in its entirety by reference may be used.

For example, to test a sample using Raman microscopy and in particularconfocal Raman microscopy, it is understood that to get appropriateRaman high resolution spectra sufficient acquisition time, laser power,laser wavelength, sample step size and microscope objective need to beoptimized. For example a sample (a coated stent) is prepared asdescribed herein. Alternatively, a coated coupon could be tested in thismethod. Maps are taken on the coating using Raman microscopy. A WITecCRM 200 scanning confocal Raman microscope using a Nd:YAG laser at 532nm is applied in the Raman imaging mode. The laser light is focused uponthe sample using a 100× dry objective (numerical aperture 0.90), and thefinely focused laser spot is scanned into the sample. As the laser scansthe sample, over each 0.33 micron interval a Raman spectrum with highsignal to noise is collected using 0.3 seconds of integration time. Eachconfocal cross-sectional image of the coatings displays a region 70 μmwide by 10 μm deep, and results from the gathering of 6300 spectra witha total imaging time of 32 min.

Multivariate analysis using reference spectra from samples of rapamycin(amorphous and crystalline) and polymer are used to deconvolve thespectral data sets, to provide chemical maps of the distribution.

Infrared (IR) Spectroscopy for In-Vitro Testing

Infrared (IR) Spectroscopy such as FTIR and ATR-IR are well utilizedtechniques that can be applied to show, for example, the quantitativedrug content, the distribution of the drug in the sample coating, thequantitative polymer content in the coating, and the distribution ofpolymer in the coating. Infrared (IR) Spectroscopy such as FTIR andATR-IR can similarly be used to show, for example, drug crystallinity.The following table lists the typical IR materials for variousapplications. These IR materials are used for IR windows, diluents orATR crystals.

MATERIAL NACL KBR CSI AGCL GE ZNSE DIAMOND Transmission 40,000 40,00040,000 25,000 5,500 20,000 40,000 range (cm-1) ~625 ~400 ~200 ~360 ~625~454 ~2,500 & 1667-33 Water sol 35.7 53.5 44.4 Insol. Insol. Insol.Insol. (g/100 g, 25° C.) Attacking Wet Wet Wet Ammonium H2SO4, Acids,K2Cr2Os, materials Solvents Solvents Solvents Salts aqua strong conc.regin alkalies, H2SO4 chlorinated solvents

In one test, a coupon of crystalline ZnSe is coated by the processesdescribed herein, creating a PDPDP (Polymer, Drug, Polymer, Drug,Polymer) layered coating that is about 10 microns thick. The coatedcoupon is analyzed using FTIR. The resulting spectrum shows crystallinedrug as determined by comparison to the spectrum obtained for thecrystalline form of a drug standard (i.e. a reference spectrum).

Differential Scanning Calorimetry (DSC)

DSC can provide qualitative evidence of the crystallinity of the drug(e.g. rapamycin) using standard DSC techniques obvious to one of skilledin the art. Crystalline melt can be shown using this analytical method(e.g. rapamycin crystalline melting—at about 185° C. to 200° C., andhaving a heat of fusion at or about 46.8 J/g). The heat of fusiondecreases with the percent crystallinity. Thus, the degree ofcrystallinity could be determined relative to a pure sample, or versus acalibration curve created from a sample of amorphous drug spiked andtested by DSC with known amounts of crystalline drug. Presence (atleast) of crystalline drug on a stent could be measured by removing(scraping or stripping) some drug from the stent and testing the coatingusing the DSC equipment for determining the melting temperature and theheat of fusion of the sample as compared to a known standard and/orstandard curve.

Confocal Raman Microscopy

Confocal Raman Microscopy can provide nondestructive depth analysis andallows coating specific Raman spectral features to be obtained (Bugay etal., “Raman Analysis of Pharmaceuticals,” in “Applications ofVibrational Spectroscopy in Pharmaceutical Research and Development,”Ed. Pivonka, D. E., Chalmers, J. M., Griffiths, P. R. (2007) Wiley andSons). In confocal Raman microscopy an aperture is place in a focalplace of the collected beam. This limitation defines a shallow portionof the depth of field and thereby provides definition of the z-axisspatial resolution for data collection. By adjusting the aperture andmoving the focus within the sample, the sampling position within thesample moves. Moving the sample focus from the top surface, deeper intothe specimen facilitates nondestructive depth analysis.

Example 13 Coating Uniformity

The ability to uniformly coat devices, e.g., pre- and post-expansionstents, and balloons, with controlled composition and thickness usingelectrostatic capture in a rapid expansion of supercritical solution(RESS) experimental series has been demonstrated.

Scanning Electron Microscopy (SEM)

Devices are observed by SEM using a Hitachi S-4800 with an acceleratingvoltage of 800V. Various magnifications are used to evaluate theintegrity, especially at high strain regions. SEM can provide top-downand cross-section images at various magnifications. Coating uniformityand thickness can also be assessed using this analytical technique.

Pre- and post-inflation balloons, for example, may be observed by SEMusing a Hitachi S-4800 with an accelerating voltage of 800V. Variousmagnifications may be used to evaluate the integrity of the layers, andor of the coating.

Scanning Electron Microscopy (SEM) with Focused Ion Beam (FIB)

Devices as described herein, and or produced by methods described hereinare visualized using SEM-FIB analysis. Alternatively, a coated couponcould be tested in this method. Focused ion beam FIB is a tool thatallows precise site-specific sectioning, milling and depositing ofmaterials. FIB can be used in conjunction with SEM, at ambient or cryoconditions, to produce in-situ sectioning followed by high-resolutionimaging. Cross-sectional FIB images may be acquired, for example, at7000× and/or at 20000× magnification. An even coating of consistentthickness is visible.

Optical Microscopy

An optical microscope may be used to create and inspect the devices andto empirically survey the coating of the substrate (e.g. coatinguniformity). Nanoparticles of the drug and/or the polymer can be seen onthe surfaces of the substrate using this analytical method. Followingsintering, the coatings can be see using this method to view the coatingconformality and for evidence of crystallinity of the drug.

Example 14 Total Drug Content on Coated Stent (Used or Unused)

Determination of the total content of the active agent in a coatedsubstrate may be tested using techniques described herein as well asother techniques obvious to one of skill in the art, for example usingGPC and HPLC techniques to extract the drug from the coated substrateand determine the total content of drug in the sample.

UV-VIS can be used to quantitatively determine the mass of rapamycin (oranother active agent) coated onto the substrates. A UV-Vis spectrum ofRapamycin can be shown and a Rapamycin calibration curve can beobtained, (e.g. λ @ 277 nm in ethanol). Rapamycin is then dissolved fromthe coated substrate in ethanol, and the drug concentration and masscalculated.

In one test, the total amount of rapamycin (or another active agent)present in units of micrograms per substrate is determined by reversephase high performance liquid chromatography with UV detection(RP-HPLC-UV). The analysis is performed with modifications ofliterature-based HPLC methods for rapamycin (or the other active agent)that would be obvious to a person of skill in the art. The average drugcontent of samples (n=10) from devices comprising stents and coatings asdescribed herein, and/or methods described herein are tested.

Further understanding of the present invention may be gained throughcontemplation of the numbered embodiments below.

-   1. A biomedical implant, comprising:    -   a tubular scaffold comprising a plurality of polymer struts,        wherein the polymer struts are interconnected and define a        plurality of deformable cells,    -   wherein the polymer struts have an average thickness of no more        than 150 μm, and    -   wherein the polymer struts comprise a fiber-reinforced polymer        composite material.-   2. The biomedical implant of embodiment 1, wherein the tubular    scaffold maintains at least 50% of its nominal luminal cross    sectional area under a pressure load of 50 mmHg.-   3. The biomedical implant of embodiment 1, wherein the tubular    scaffold maintains at least 80% of its nominal luminal cross    sectional area under a pressure load of 50 mmHg.-   4. The biomedical implant of embodiment 1, wherein the tubular    scaffold maintains at least 50% of its nominal luminal cross    sectional area under a pressure load of 50 mmHg upon 3 months of    exposure to saline in vitro.-   5. The biomedical implant of embodiment 1, wherein the tubular    scaffold maintains at least 50% of its nominal luminal cross    sectional area under a pressure load of 50 mmHg upon 3 months in    vivo.-   6. The biomedical implant of embodiment 1, wherein the tubular    scaffold maintains at least 50% of its nominal luminal cross    sectional area under a pressure load of 50 mmHg upon 6 months of    exposure to saline in vitro.-   7. The biomedical implant of embodiment 1, wherein the tubular    scaffold maintains at least 50% of its nominal luminal cross    sectional area under a pressure load of 50 mmHg upon 6 months in    vivo.-   8. The biomedical implant of embodiment 1, wherein at least 80% of    the polymer struts are bioabsorbed within 2 years after deployment    in vivo.-   9. The biomedical implant of embodiment 1, wherein at least 80% of    the polymer struts are bioabsorbed within 1 year after deployment in    vivo.-   10. The biomedical implant of embodiment 1, wherein the polymer    struts have an average thickness of no more than 120 μm.-   11. The biomedical implant of embodiment 1, wherein the polymer    struts have an average thickness of no more than 90 μm.-   12. The biomedical implant of embodiment 1, wherein the    fiber-reinforced polymer composite material comprise a bioabsorbable    polymer material and a reinforcement fiber material.-   13. The biomedical implant of embodiment 12, wherein the    reinforcement fiber material is carbon fiber material, carbon    nanotube material, bioabsorbable glass material, or combinations    thereof.-   14. The biomedical implant of embodiment 13, wherein carbon nanotube    material is a multi-wall carbon nanotube material.-   15. The biomedical implant of embodiment 12, wherein the    reinforcement fiber material is distributed throughout the polymer    struts.-   16. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material has a tensile modulus    that is at least five times of a tensile modulus of the    bioabsorbable polymer.-   17. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material has a tensile modulus    that is at least three times of a tensile modulus of the    bioabsorbable polymer.-   18. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material has a tensile modulus    that is at least two times of a tensile modulus of the bioabsorbable    polymer.-   19. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material has a tensile strength    that is at least five times of a tensile strength of the    bioabsorbable polymer.-   20. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material has a tensile strength    that is at least three times of a tensile strength of the    bioabsorbable polymer.-   21. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material has a tensile strength    that is at least two times of a tensile strength of the    bioabsorbable polymer.-   22. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material comprises from 0.1 wt %    to 15 wt % of the reinforcement fiber material.-   23. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material comprises from 0.1 wt %    to 10 wt % of the reinforcement fiber material.-   24. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material comprises from 0.1 wt %    to 5 wt % of the reinforcement fiber material.-   25. The biomedical implant of embodiment 12, wherein the    fiber-reinforced polymer composite material comprises from 0.1 wt %    to 1.5 wt % of the reinforcement fiber material.-   26. The biomedical implant of embodiment 12, wherein the    bioabsorbable polymer material is selected from the group consisting    of polylactides (PLA); poly(lactide-co-glycolide) (PLGA);    polyanhydrides; polyorthoesters;    poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA);    poly(l-lactide) (LPLA); poly(d-lactide) (DPLA); polyglycolide (PGA);    poly(dioxanone) (PDO); poly(glycolide-co-trimethylene carbonate)    (PGA-TMC); poly(l-lactide-co-glycolide) (PGA-LPLA);    poly(dl-lactide-co-glycolide) (PGA-DLPLA);    poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);    poly(glycolide-co-trimethylene carbonate-co-dioxanone)    (PDO-PGA-TMC), poly(lactic acid-co-caprolactone) (PLACL), and    mixtures or co-polymers thereof.-   27. The biomedical implant of embodiment 26, wherein the    bioabsorbable polymer material is PLGA.-   28. The biomedical implant of embodiment 27, wherein the PLGA has a    ratio of lactic acid monomer to glycolic acid monomer ranging from    72:28 to 78:22.-   29. The biomedical implant of embodiment 27, wherein the PLGA has a    ratio of lactic acid monomer to glycolic acid monomer ranging from    62:38 to 68:32.-   30. The biomedical implant of embodiment 27, wherein the PLGA has a    ratio of lactic acid monomer to glycolic acid monomer ranging from    47:53 to 53:47.-   31. The biomedical implant of embodiment 27, wherein the PLGA has a    weight average molecular weight of about 8,000 Dalton to about    12,000 Dalton.-   32. The biomedical implant of embodiment 27, wherein the PLGA has a    weight average molecular weight of about 12,000 Dalton to about    16,000 Dalton.-   33. The biomedical implant of embodiment 26, wherein the    bioabsorbable polymer material has a weight average molecular weight    of at least 90,000 Dalton, and optionally at least 100,000 Dalton.-   34. The biomedical implant of embodiment 33, wherein the gel-spun    polymer material is LPLA having a weigh average molecular weight of    at least 100,000 Dalton.-   35. The biomedical implant of embodiment 26, wherein the    bioabsorbable polymer material is PLA, LPLA, or PGA.-   36. The biomedical implant of embodiment 12, wherein the polymer    struts have anisotropic elastic modulus.-   37. The biomedical implant of embodiment 36, wherein the polymer    struts have an average longitudinal elastic modulus and an average    lateral elastic modulus, the average longitudinal elastic modulus    being greater than the average lateral elastic modulus.-   38. The biomedical implant of embodiment 36, wherein the average    longitudinal elastic modulus is at least three times the average    lateral elastic modulus.-   39. The biomedical implant of embodiment 36, wherein the average    longitudinal elastic modulus is at least five times the average    lateral elastic modulus.-   40. The biomedical implant of embodiment 36, wherein the average    longitudinal elastic modulus is at least ten times the average    lateral elastic modulus.-   41. The biomedical implant of embodiment 12, wherein more than 50%    of the reinforcement fiber material in the polymer struts are    longitudinally aligned.-   42. The biomedical implant of embodiment 12, wherein more than 70%    of the reinforcement fiber material in the polymer struts are    longitudinally aligned.-   43. The biomedical implant of embodiment 12, wherein more than 90%    of the reinforcement fiber material in the polymer struts are    longitudinally aligned.-   44. The biomedical implant of embodiment 1, wherein the polymer    struts have an average deformation angle of at least 60 degrees.-   45. The biomedical implant of embodiment 1, wherein the polymer    struts have an average deformation angle of at least 45 degrees.-   46. The biomedical implant of embodiment 1, wherein the polymer    struts are not structurally reinforced with a metal material.-   47. The biomedical implant of embodiment 1, wherein the polymer    struts comprises a polymer material selected from the group    consisting of polycarboxylic acids, cellulosic polymers, proteins,    polypeptides, polyvinylpyrrolidone, maleic anhydride polymers,    polyamides, polyvinyl alcohols, polyethylene oxides,    glycosaminoglycans, polysaccharides, polyesters, aliphatic    polyesters, polyurethanes, polystyrenes, copolymers, silicones,    silicone containing polymers, polyalkyl siloxanes, polyorthoesters,    polyanhydrides, copolymers of vinyl monomers, polycarbonates,    polyethylenes, polypropytenes, polylactic acids, polylactides,    polyglycolic acids, polyglycolides, polylactide-co-glycolides,    polycaprolactones, poly(e-caprolactone)s, polyhydroxybutyrate    valerates, polyacrylamides, polyethers, polyurethane dispersions,    polyacrylates, acrylic latex dispersions, polyacrylic acid,    polyalkyl methacrylates, polyalkylene-co-vinyl acetates,    polyalkylenes, aliphatic polycarbonates polyhydroxyalkanoates,    polytetrahaloalkylenes, poly(phosphasones), polytetrahaloalkylenes,    poly(phosphasones), and mixtures, combinations, and copolymers    thereof.-   48. The biomedical implant of embodiment 1, wherein the tubular    scaffold is expandable from an undeployed diameter to a nominal    diameter without affecting the structural integrity of the tubular    scaffold-   49. The biomedical implant of embodiment 48, wherein the tubular    scaffold is further expandable from the nominal diameter to an    over-deployed diameter without affecting the structural integrity of    the tubular scaffold.-   50. The biomedical implant of embodiment 49, wherein the    over-deployed diameter is about 1.0 mm greater than the nominal    diameter.-   51. The biomedical implant of embodiment 49, wherein the    over-deployed diameter is about 0.5 mm greater than the nominal    diameter.-   52. The biomedical implant of embodiment 48, wherein the tubular    scaffold is expandable by an inflatable balloon positioned within    the tubular scaffold.-   53. The biomedical implant of embodiment 52, wherein the tubular    scaffold has a nominal diameter of 2.25 mm at nominal balloon    pressure.-   54. The biomedical implant of embodiment 52, wherein the tubular    scaffold has a nominal diameter of 2.5 mm at nominal balloon    pressure.-   55. The biomedical implant of embodiment 52, wherein the tubular    scaffold has a nominal diameter of 3.0 mm at nominal balloon    pressure.-   56. The biomedical implant of embodiment 52, wherein the tubular    scaffold has a nominal diameter of 3.5 mm at nominal balloon    pressure.-   57. The biomedical implant of embodiment 52, wherein the tubular    scaffold has a deployed diameter of 4.0 mm at nominal balloon    pressure.-   58. The biomedical implant of embodiment 52, wherein the tubular    scaffold has a nominal diameter of 4.5 mm at nominal balloon    pressure.-   59. The biomedical implant of embodiment 48, wherein the polymer    struts comprise a shape-memory polymer and wherein tubular scaffold    is self-expandable.-   60. The biomedical implant of embodiment 59, wherein the tubular    scaffold is self-expandable upon change in temperature.-   61. The biomedical implant of embodiment 59, wherein the tubular    scaffold is self-expandable upon change in crystallinity of the    shape-memory polymer.-   62. The biomedical implant of embodiment 1, wherein the tubular    scaffold is formed from a plurality of sinusoidal polymer fibers    comprising the plurality of polymer struts.-   63. The biomedical implant of embodiment 62, wherein the sinusoidal    polymer fibers are interconnected at a plurality of connecting    points.-   64. The biomedical implant of embodiment 1, wherein the tubular    scaffold is formed from a single polymer fiber.-   65. The biomedical implant of embodiment 64, wherein the single    polymer fiber comprises a plurality of sinusoidal sections    interconnected at a plurality of connecting points.-   66. The biomedical implant of embodiment 1, further comprising a    pharmaceutical agent incorporated to the tubular scaffold.-   67. The biomedical implant of embodiment 66, wherein the    pharmaceutical agent is a macrolide immunosuppressant.-   68. The biomedical implant of embodiment 67, wherein the macrolide    immunosuppressant is rapamycin or a derivative, a prodrug, a    hydrate, an ester, a salt, a polymorph, a derivative or an analog    thereof.-   69. The biomedical implant of embodiment 67, wherein the macrolide    immunosuppressant is selected from the group consisting of    rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),    40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,    40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin,    40-O-Allyl-rapamycin,    40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,    (2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin,    40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,    40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin,    40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,    40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,    40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,    40-O-(2-Acetoxy)ethyl-rapamycin,    40-O-(2-Nicotinoyloxy)ethyl-rapamycin,    40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin,    40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,    40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,    39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,    (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin,    28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,    40-O-(2-Acetaminoethyl)-rapamycin,    40-O-(2-Nicotinamidoethyl)-rapamycin,    40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,    40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,    40-O-(2-Tolylsulfonamidoethyl)-rapamycin,    40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,    42-Epi-(tetrazolyl)rapamycin (tacrolimus), and    42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin.-   70. The biomedical implant of embodiment 67, wherein the    pharmaceutical agent is rapamycin.-   71. The biomedical implant of embodiment 66, wherein the    pharmaceutical agent is impregnated in at least a portion of the    tubular scaffold.-   72. The biomedical implant of embodiment 71, wherein the    pharmaceutical agent is impregnated in the polymer struts.-   73. The biomedical implant of embodiment 72, wherein the    pharmaceutical agent is evenly distributed throughout the polymer    struts.-   74. The biomedical implant of embodiment 66, wherein at least a    portion of the tubular scaffold is covered with a coating comprising    the pharmaceutical agent.-   75. The biomedical implant of embodiment 74, wherein the coating    further comprises a coating polymer.-   76. The biomedical implant of embodiment 75, wherein at least 90% of    the surface area of the pharmaceutical agent is encapsulated in the    coating polymer.-   77. The biomedical implant of embodiment 75, wherein the coating    polymer comprises a bioabsorbable polymer.-   78. The biomedical implant of embodiment 77, wherein the    bioabsorbable polymer is selected from the group consisting of    polylactides (PLA); poly(lactide-co-glycolide) (PLGA);    polyanhydrides; polyorthoesters;    poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA);    poly(l-lactide) (LPLA); polyglycolide (PGA); poly(dioxanone) (PDO);    poly(glycolide-co-trimethylene carbonate) (PGA-TMC);    poly(l-lactide-co-glycolide) (PGA-LPLA);    poly(dl-lactide-co-glycolide) (PGA-DLPLA);    poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);    poly(glycolide-co-trimethylene carbonate-co-dioxanone)    (PDO-PGA-TMC), polyarginine, and mixtures or co-polymers thereof.-   79. The biomedical implant of embodiment 77, wherein the    biodegradable polymer is selected from the group consisting of PLGA,    polyarginine, and mixtures thereof.-   80. The biomedical implant of embodiment 1, wherein the biomedical    implant is a vascular stent.-   81. The biomedical implant of embodiment 80, wherein the biomedical    implant is a coronary artery stent.-   82. The biomedical implant of embodiment 80, wherein the biomedical    implant is a peripheral artery stent.-   83. The biomedical implant of embodiment 1, wherein the biomedical    implant is a non-vascular stent.-   84. The biomedical implant of embodiment 83, wherein the    non-vascular stent is selected from esophageal stent, biliary stent,    duodenal stent, colonic stent, and pancreatic stent.-   85. A method of forming a biomedical implant, comprising:    -   forming one or more polymer fibers comprising a bioabsorbable        polyester material and a reinforcement fiber material; and    -   interconnecting the polymer fibers to form a tubular scaffold,        the tubular scaffold comprising a plurality of interconnected        polymer struts to define a plurality of deformable cells,        wherein the polymer struts have an average thickness of no more        than 150 μm.-   86. The method of embodiment 85, wherein the tubular scaffold    maintains at least 50% of its nominal luminal cross sectional area    under a pressure load of at least 50 mmHg.-   87. The method of embodiment 85, wherein the tubular scaffold    maintains at least 80% of its nominal luminal cross sectional area    under a pressure load of at least 50 mmHg.-   88. The method of embodiment 85, wherein the reinforcement fiber    material is carbon fiber material, carbon nanotube material,    bioabsorbable glass material, or combinations thereof.-   89. The method of embodiment 88, wherein the carbon nanotube    material is a multi-wall carbon nanotube material.-   90. The method of embodiment 85, wherein the polymer fibers comprise    from 0.1 wt % to 15 wt % of the reinforcement fiber material.-   91. The method of embodiment 85, wherein the polymer fibers comprise    from 0.1 wt % to 10 wt % of the reinforcement fiber material.-   92. The method of embodiment 85, wherein the polymer fibers comprise    from 0.1 wt % to 5 wt % of the reinforcement fiber material.-   93. The method of embodiment 85, wherein the polymer fibers comprise    from 0.1 wt % to 1.5 wt % of the reinforcement fiber material.-   94. The method of embodiment 85, wherein the polyester is selected    from the group consisting of polylactides (PLA);    poly(lactide-co-glycolide) (PLGA); polyanhydrides; polyorthoesters;    poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA);    poly(l-lactide) (LPLA); poly(d-lactide) (DPLA); polyglycolide (PGA);    poly(dioxanone) (PDO); poly(glycolide-co-trimethylene carbonate)    (PGA-TMC); poly(l-lactide-co-glycolide) (PGA-LPLA);    poly(dl-lactide-co-glycolide) (PGA-DLPLA);    poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);    poly(glycolide-co-trimethylene carbonate-co-dioxanone)    (PDO-PGA-TMC), poly(lactic acid-co-caprolactone) (PLACL), and    mixtures or co-polymers thereof.-   95. The method of embodiment 85, wherein the polyester is PLGA.-   96. The method of embodiment 85, wherein the polyester is PLA or    LPLA.-   97. A method of making a bioabsorbable tubular scaffold, the method    comprising    -   forming a composition comprising a bioabsorbable polyester        material and a reinforcement fiber material;    -   extruding the composition to form a polymer tube, wherein the        polymer tube has an average wall thickness of no more than 150        μm; and    -   removing a portion of the polymer tube to form a scaffold        comprising interconnected struts.-   98. The method of embodiment 97, wherein the tubular scaffold    maintains at least 50% of its nominal luminal cross sectional area    under a pressure load of at least 50 mmHg.-   99. The method of embodiment 97, wherein the tubular scaffold    maintains at least 80% of its nominal luminal cross sectional area    under a pressure load of at least 50 mmHg.-   100. The method of embodiment 97, wherein the reinforcement fiber    material is carbon fiber material, carbon nanotube material,    bioabsorbable glass material, or combinations thereof.-   101. The method of embodiment 100, wherein the carbon nanotube    material is a multi-wall carbon nanotube material.-   102. The method of embodiment 97, wherein the polymer tube comprises    from 0.1 wt % to 15 wt % of the reinforcement fiber material.-   103. The method of embodiment 97, wherein the polymer tube comprises    from 0.1 wt % to 10 wt % of the reinforcement fiber material.-   104. The method of embodiment 97, wherein the polymer tube comprises    from 0.1 wt % to 5 wt % of the reinforcement fiber material.-   105. The method of embodiment 97, wherein the polymer tube comprises    from 0.1 wt % to 1.5 wt % of the reinforcement fiber material.-   106. The method of embodiment 97, wherein the polyester is selected    from the group consisting of polylactides (PLA);    poly(lactide-co-glycolide) (PLGA); polyanhydrides; polyorthoesters;    poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA);    poly(l-lactide) (LPLA); poly(d-lactide) (DPLA); polyglycolide (PGA);    poly(dioxanone) (PDO); poly(glycolide-co-trimethylene carbonate)    (PGA-TMC); poly(l-lactide-co-glycolide) (PGA-LPLA);    poly(dl-lactide-co-glycolide) (PGA-DLPLA);    poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);    poly(glycolide-co-trimethylene carbonate-co-dioxanone)    (PDO-PGA-TMC), poly(lactic acid-co-caprolactone) (PLACL), and    mixtures or co-polymers thereof.-   107. The method of embodiment 97, wherein the polyester is PLGA.-   108. The method of embodiment 97, wherein the polyester is PLA or    LPLA.-   109. The method of embodiment 97, wherein the removing is selected    from laser-cutting, photochemical etching, and water-jetting.-   110. The biomedical implant of embodiment 13, wherein the    reinforcement fiber material comprises one or more surface    functionalities to facilitate intermolecular interaction between the    bioabsorbable polymer material and the reinforcement fiber material.-   111. The biomedical implant of embodiment 13, wherein the one or    more surface functionalities are selected from —COOH, —OH, or    combination thereof.-   112. The biomedical implant of embodiment 13, wherein the    reinforcement fiber material is multi-wall carbon nanotube material.-   113. The method of embodiment 88, wherein the reinforcement fiber    material comprises one or more surface functionalities to facilitate    intermolecular interaction between the bioabsorbable polymer    material and the reinforcement fiber material.-   114. The method of embodiment 88, wherein the one or more surface    functionalities are selected from —COOH, —OH, or combination    thereof.-   115. The method of embodiment 88, wherein the reinforcement fiber    material is multi-wall carbon nanotube material.-   116. The method of embodiment 100, wherein the reinforcement fiber    material comprises one or more surface functionalities to facilitate    intermolecular interaction between the bioabsorbable polymer    material and the reinforcement fiber material.-   117. The method of embodiment 100, wherein the one or more surface    functionalities are selected from —COOH, —OH, or combination    thereof.-   118. The method of embodiment 100, wherein the reinforcement fiber    material is multi-wall carbon nanotube material.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1. A biomedical implant, comprising: a tubular scaffold comprising aplurality of polymer struts, wherein the polymer struts areinterconnected and define a plurality of deformable cells, wherein thepolymer struts have an average thickness of no more than 150 μm, andwherein the polymer struts comprise a fiber-reinforced polymer compositematerial, the fiber-reinforced polymer composite material comprising abioabsorbable polymer material and a reinforcement fiber material abioabsorbable polymer material and a reinforcement fiber material. 2.The biomedical implant of claim 1, wherein the reinforcement fibermaterial is carbon fiber, carbon nanotube, bioabsorbable glass, orcombinations thereof.
 3. The biomedical implant of claim 13, wherein thereinforcement fiber material is carbon fiber.
 4. The biomedical implantof claim 12, wherein the reinforcement fiber material is distributedthroughout the polymer struts.
 5. The biomedical implant of claim 12,wherein the fiber-reinforced polymer composite material has a tensilemodulus that is at least five times, at least three times, or at leasttwo times of a tensile modulus of the bioabsorbable polymer.
 6. Thebiomedical implant of claim 12, wherein the fiber-reinforced polymercomposite material has a tensile strength that is at least five times,at least three times, or at least two times of a tensile strength of thebioabsorbable polymer.
 7. The biomedical implant of claim 12, whereinthe fiber-reinforced polymer composite material comprises from 0.1 wt %to 15 wt % of the reinforcement fiber material.
 8. The biomedicalimplant of claim 12, wherein the bioabsorbable polymer material isselected from the group consisting of polylactides (PLA);poly(lactide-co-glycolide) (PLGA); polyanhydrides; polyorthoesters;poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA);poly(l-lactide) (LPLA); poly(d-lactide) (DPLA); polyglycolide (PGA);poly(dioxanone) (PDO); poly(glycolide-co-trimethylene carbonate)(PGA-TMC); poly(l-lactide-co-glycolide) (PGA-LPLA);poly(dl-lactide-co-glycolide) (PGA-DLPLA); poly(l-lactide-co-dl-lactide)(LPLA-DLPLA); poly(glycolide-co-trimethylene carbonate-co-dioxanone)(PDO-PGA-TMC), poly(lactic acid-co-caprolactone) (PLACL), and mixturesor co-polymers thereof.
 9. The biomedical implant of claim 26, whereinthe bioabsorbable polymer material is PLGA.
 10. The biomedical implantof claim 12, wherein the polymer struts have anisotropic elasticmodulus.
 11. The biomedical implant of claim 36, wherein the polymerstruts have an average longitudinal elastic modulus and an averagelateral elastic modulus, the average longitudinal elastic modulus beinggreater than the average lateral elastic modulus.
 12. The biomedicalimplant of claim 36, wherein the average longitudinal elastic modulus isat least three times, at least five times, or at least ten times theaverage lateral elastic modulus.
 13. The biomedical implant of claim 12,wherein more than 50%, more than 70%, or more than 90% of thereinforcement fiber material in the polymer struts are longitudinallyaligned.
 14. The biomedical implant of claim 1, wherein the polymerstruts are not structurally reinforced with a metal material.
 15. Thebiomedical implant of claim 1, further comprising a pharmaceutical agentincorporated to the tubular scaffold.
 16. The biomedical implant ofclaim 67, wherein the pharmaceutical agent is rapamycin.
 17. Thebiomedical implant of claim 71, wherein the pharmaceutical agent isimpregnated in the polymer struts.
 18. The biomedical implant of claim66, wherein at least a portion of the tubular scaffold is covered with acoating comprising the pharmaceutical agent.
 19. A method of forming abiomedical implant, comprising: forming one or more polymer fiberscomprising a bioabsorbable polyester material and a reinforcement fibermaterial; and interconnecting the polymer fibers to form a tubularscaffold, the tubular scaffold comprising a plurality of interconnectedpolymer struts to define a plurality of deformable cells, wherein thepolymer struts have an average thickness of no more than 150 μm, whereinthe reinforcement fiber material is carbon fiber, carbon nanotube,bioabsorbable glass, or combinations thereof.
 20. A method of making abioabsorbable tubular scaffold, the method comprising forming acomposition comprising a bioabsorbable polyester material and areinforcement fiber material; extruding the composition to form apolymer tube, wherein the polymer tube has an average wall thickness ofno more than 150 μm; and removing a portion of the polymer tube to forma scaffold comprising interconnected struts, wherein the reinforcementfiber material is carbon fiber, carbon nanotube, bioabsorbable glass, orcombinations thereof.